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  5. GLP-1类药物在减重与2型糖尿病治疗领域的研究进展及产业竞争分析

GLP-1类药物在减重与2型糖尿病治疗领域的研究进展及产业竞争分析

深度研究匿名用户发表于 2026年05月06日 23:1764阅读
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1. GLP-1类药物的作用机制与临床价值定位

1.1 核心作用机制

胰高糖素样肽-1（GLP-1）受体激动剂是一类模拟天然肠促胰素GLP-1作用的药物，其核心作用机制在于多方面调节葡萄糖代谢、食欲和能量平衡。GLP-1主要通过激活GLP-1受体发挥作用，这些受体广泛分布于胰腺β细胞、胃肠道、大脑、心脏、肾脏和脂肪组织等多个器官和组织 123。

GLP-1受体激动剂（单靶点）的作用机制：

  1. 葡萄糖依赖性胰岛素分泌增强： GLP-1受体激动剂可刺激胰腺β细胞在血糖升高时分泌胰岛素，从而降低血糖水平。这种作用是葡萄糖依赖性的，意味着在血糖正常或偏低时，胰岛素分泌刺激作用会减弱，从而降低低血糖的风险 124。
  2. 抑制胰高糖素分泌： GLP-1能抑制胰腺α细胞分泌胰高糖素，进一步减少肝脏葡萄糖输出，协同降低血糖 124。
  3. 延缓胃排空： GLP-1受体激动剂可减慢胃排空速度，使餐后葡萄糖吸收变缓，有助于平稳餐后血糖波动 14。
  4. 抑制食欲和促进饱腹感： GLP-1通过作用于中枢神经系统，特别是下丘脑区域（如弓状核），减少食物摄入，并增加饱腹感，从而导致体重减轻 15678。司美格鲁肽通过与GLP-1受体结合，在下丘脑弓状核等多个脑区发挥作用，调节食物偏好和摄入，而不降低能量消耗 59。
  5. 脂肪代谢调节： GLP-1还参与调节脂质代谢，通过抑制脂肪合成、促进脂肪分化、增强胆固醇代谢以及促进脂肪棕色化等方式发挥作用，对肥胖、非酒精性脂肪肝病和动脉粥样硬化等代谢性疾病具有潜在益处 101112。

GIP/GLP-1受体双靶点激动剂的作用机制：
替尔泊肽（Tirzepatide）是首个获批的双靶点GIP（葡萄糖依赖性促胰岛素多肽）和GLP-1受体激动剂，其作用机制更为复杂和全面 313。它结合了GLP-1的上述作用，并额外引入了GIP的药理活性：

  1. GIP受体激活： GIP也是一种肠促胰素，与GLP-1共同作用于胰腺β细胞，增强胰岛素分泌。GIP还在脂肪组织中发挥作用，影响脂肪细胞功能和能量储存 21415。
  2. 协同降糖和减重： 替尔泊肽通过同时激活GIP和GLP-1受体，在降低血糖和减轻体重方面表现出优于单一GLP-1受体激动剂的疗效 1316。GIP和GLP-1共同调节食物摄入、脂肪生成和脂肪分解，有助于维持代谢稳态 1114。
  3. 对脂肪组织的影响： GIP受体激动剂在空腹状态下能增强脂质释放，而在进食状态下与胰岛素协同作用，促进葡萄糖和脂质的清除，从而调节脂肪细胞的营养代谢 17。研究表明，替尔泊肽对GIP受体的激活程度高于GLP-1受体，且在GLP-1受体上表现出对cAMP生成的偏向性激动作用，而非β-arrestin募集，这可能增强了其胰岛素分泌的效力 18。
  4. 改善胰岛素敏感性： 替尔泊肽能够显著改善胰岛素敏感性和胰岛素分泌反应，这与更低的餐后胰岛素和胰高糖素浓度相关，进一步提升了其降糖效果 13。

1.2 临床价值定位

GLP-1类药物在2型糖尿病和肥胖症治疗中展现出显著的临床优势，使其在现代治疗指南中占据了重要地位。与传统的降糖及减重药物相比，GLP-1受体激动剂及其双靶点激动剂在疗效、安全性及多重获益方面具有独特优势。

相较于传统降糖药物的优势：

  1. 低血糖风险低： 传统降糖药物如磺脲类和胰岛素，常伴随较高低血糖风险。GLP-1类药物的胰岛素促分泌作用是葡萄糖依赖性的，即仅在血糖升高时促进胰岛素分泌，从而显著降低了低血糖的发生率 1920。
  2. 体重减轻而非增加： 大多数传统降糖药物（如胰岛素、磺脲类、噻唑烷二酮类）会导致体重增加，这对于本身就常伴有超重或肥胖的2型糖尿病患者而言是一个不利因素 2122。GLP-1受体激动剂通过抑制食欲和延缓胃排空，能够有效减轻体重，这对改善患者整体代谢状况至关重要 1192123。
  3. 心血管和肾脏保护作用： 大量临床研究表明，GLP-1受体激动剂具有明确的心血管和肾脏保护作用，能够降低主要不良心血管事件（MACE）、心血管死亡、非致死性心肌梗死及肾脏事件的风险 24252627。这使得它们成为伴有心血管疾病或高风险、慢性肾病患者的优选药物。相比之下，部分传统降糖药在这方面缺乏类似证据，甚至可能增加某些心血管风险 25。
  4. 改善血脂谱： GLP-1类药物，特别是双靶点激动剂，还被观察到能改善血脂谱，包括降低总胆固醇、低密度脂蛋白（LDL）胆固醇、甘油三酯和游离脂肪酸水平，这进一步有助于降低心血管风险 142324。

相较于传统减重药物的优势：

  1. 减重效果显著： GLP-1类药物，尤其是司美格鲁肽和替尔泊肽，其减重效果接近甚至优于部分减重手术，远超传统减重药物 2829。替尔泊肽在体重管理方面效果最为显著，在72周内平均减重可达21% 28。
  2. 改善代谢并发症： 除了直接减重，GLP-1类药物还能显著改善肥胖相关的代谢并发症，如高血压、血脂异常和胰岛素抵抗，为患者带来全面的健康益处 1430。
  3. 安全性相对较高： 虽然GLP-1类药物可能引起胃肠道不适等不良反应，但相比一些因安全性问题被撤市的传统减重药物（如部分作用于中枢神经系统的食欲抑制剂），其长期安全性已被广泛证实 21。

在2型糖尿病诊疗指南中的推荐等级与适用人群：
鉴于上述优势，GLP-1类药物在国内外2型糖尿病诊疗指南中的推荐级别不断提升：

  • 作为二线或更早的治疗选择： 对于无法通过生活方式干预和二甲双胍单药治疗有效控制血糖的患者，GLP-1受体激动剂常被推荐作为二线治疗药物 4。
  • 伴有心血管疾病或慢性肾病患者的首选： 对于伴有动脉粥样硬化性心血管疾病、心力衰竭风险高或慢性肾病的2型糖尿病患者，指南强烈推荐使用具有心血管和肾脏获益证据的GLP-1受体激动剂（与SGLT-2抑制剂一同） 2627。
  • 伴有肥胖或超重患者： 对于伴有超重或肥胖的2型糖尿病患者，GLP-1受体激动剂因其显著的减重效果而受到青睐，有助于实现体重管理目标并改善代谢指标 2021。

在肥胖症诊疗指南中的推荐等级与适用人群：
随着司美格鲁肽和替尔泊肽等药物获批用于肥胖或超重伴有合并症的治疗，GLP-1类药物在肥胖症管理中发挥着越来越重要的作用：

  • 作为生活方式干预的辅助治疗： 对于BMI≥30 kg/m²（肥胖）或BMI≥27 kg/m²且伴有至少一种体重相关合并症（如高血压、血脂异常、2型糖尿病等）的成年患者，在结合饮食控制和运动等生活方式干预无效后，GLP-1类药物被推荐用于长期体重管理 28。
  • 长期维持体重减轻： 临床实践表明，单独的生活方式干预往往难以实现并维持显著的体重减轻。GLP-1类药物为患者提供了长期管理体重的有效药理学手段，有助于预防体重反弹并持续改善健康状况 28。

然而，需要注意的是，尽管GLP-1类药物具有显著优势，但其注射给药方式（口服剂型正在开发中）以及可能引起的胃肠道不良反应（如恶心、呕吐等）仍是部分患者依从性的挑战 419。此外，这些药物的成本也可能是影响其广泛应用的一个因素 31。

2. 核心品种的临床研究进展

2.1 司美格鲁肽的临床研究数据

司美格鲁肽（Semaglutide）作为一种长效GLP-1受体激动剂，已开发出皮下注射剂型和口服剂型，并在2型糖尿病和肥胖症治疗领域取得了显著的临床成功。其皮下注射剂型尤其在降糖和减重方面展现出卓越的疗效，并在一系列全球性III期临床试验（SUSTAIN和STEP项目）中得到了验证。

2型糖尿病治疗领域（SUSTAIN项目）：
在SUSTAIN（Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes）III期临床试验项目中，每周一次皮下注射司美格鲁肽在2型糖尿病患者中表现出显著的降糖和减重效果。

  • 降糖疗效： SUSTAIN项目涵盖了多种临床场景，包括仅通过饮食和运动管理的早期2型糖尿病患者，以及已接受1至3种口服降糖药治疗但血糖控制不佳的患者，乃至接受胰岛素治疗的晚期患者。研究结果显示，每周一次皮下注射1.0 mg司美格鲁肽，在30-56周后能使糖化血红蛋白（HbA1c）降低1.5%至1.8% 32。这一降幅显著优于西格列汀（Sitagliptin）、利拉鲁肽（Liraglutide）、艾塞那肽缓释剂（Exenatide extended release）、度拉鲁肽（Dulaglutide）、卡格列净（Canagliflozin）或甘精胰岛素（Insulin glargine）等多种活性对照药物 32。
  • 减重疗效： 除了降糖，皮下注射司美格鲁肽也显著减轻了患者体重。在SUSTAIN项目中，司美格鲁肽的减重效果显著优于所有测试的活性对照药物 32。具体来说，与安慰剂相比，司美格鲁肽能带来显著的体重减轻，这对于伴有超重或肥胖的2型糖尿病患者而言具有重要的临床意义。

单纯肥胖减重领域（STEP项目）：
司美格鲁肽皮下注射剂型（商品名为Wegovy）被批准用于肥胖或超重患者的体重管理，其临床证据主要来自STEP（Semaglutide Treatment Effect in People with Obesity）III期临床试验项目。该项目旨在评估司美格鲁肽在非糖尿病肥胖患者中的减重效果和安全性。

  • 显著的体重减轻： STEP项目中的四项III期临床试验共纳入了约5000名超重或肥胖受试者，主要为BMI≥27 kg/m²的患者。结果显示，每周一次皮下注射2.4 mg司美格鲁肽，与安慰剂相比，能剂量依赖性地显著减轻体重 33。一项系统综述和荟萃分析指出，在非糖尿病肥胖患者中，皮下注射司美格鲁肽（2.4 mg每周一次）可使体重平均减少11.85% 34。另一项针对长期疗效的系统综述显示，在至少68周的随访中，司美格鲁肽与安慰剂相比，可使相对体重显著减少12.1%，绝对体重减少12.3 kg 35。
  • 达到临床意义体重减轻的比例： 在STEP项目中，接受司美格鲁肽治疗的患者中有更高比例的人实现了5%、10%甚至20%的体重减轻。例如，在最长随访期内，33.4%的司美格鲁肽治疗组患者达到了≥20%的体重减轻，而安慰剂组仅为2.2% 35。
  • 对心脏代谢风险因素的改善： 司美格鲁肽的减重效果不仅限于体重本身，还能带来血压、血脂等心脏代谢指标的改善，从而降低肥胖相关并发症的风险 36。
  • 安全性： 在体重管理方面，司美格鲁肽最常见的不良反应是胃肠道事件，如恶心、呕吐、腹泻和便秘，这些事件通常为轻中度且呈一过性 333435。虽然胃肠道不良事件的发生率在司美格鲁肽组高于安慰剂组（风险比为1.59），并可能导致部分患者停药（停药风险比为2.19），但大多数患者能够耐受 34。

不同给药剂量的疗效差异：
司美格鲁肽在2型糖尿病治疗中常用的剂量为0.5 mg和1.0 mg每周一次，而在肥胖管理中则常使用更高剂量2.4 mg每周一次。

  • 剂量与疗效的正相关性： 临床研究表明，司美格鲁肽的降糖和减重效果与剂量呈正相关。更高剂量的司美格鲁肽通常能带来更显著的HbA1c降低和体重减轻。例如，在糖尿病患者中，1.0 mg剂量的降糖和减重效果优于0.5 mg剂量 32。在肥胖患者中，2.4 mg剂量的减重效果显著优于较低剂量，也高于糖尿病治疗剂量的减重效果 3334。
  • 安全性与剂量的关系： 随着剂量的增加，胃肠道不良反应的发生率和严重程度也可能增加，因此临床上通常采用逐步增加剂量的策略（剂量滴定）以提高患者的耐受性 37。

综上所述，司美格鲁肽皮下注射剂型在2型糖尿病患者的血糖控制和体重管理方面表现出卓越的疗效，同时在非糖尿病肥胖患者中也展现了强大的减重潜力，并伴随着可接受的安全性，使其成为重要的治疗选择。

2.2 替尔泊肽的临床研究进展

替尔泊肽（Tirzepatide）是一种每周注射一次的GIP（葡萄糖依赖性促胰岛素多肽）和GLP-1（胰高糖素样肽-1）双受体激动剂，它通过同时激活这两种肠促胰素受体，在2型糖尿病和肥胖症治疗中展现出卓越的降糖和减重效果，甚至在某些方面超越了单一GLP-1受体激动剂。其临床数据主要来源于SURPASS和SURMOUNT系列临床试验。

2型糖尿病治疗领域（SURPASS项目）：
SURPASS系列临床试验全面评估了替尔泊肽在2型糖尿病患者中的疗效和安全性。

  • 降糖效果： 在SURPASS-1至SURPASS-5等关键性III期临床试验中，替尔泊肽（5 mg、10 mg和15 mg每周一次）均显示出显著且剂量依赖性的糖化血红蛋白（HbA1c）降低。例如，在多项研究中，替尔泊肽能够使HbA1c降低1.24%至2.58%，其中相当一部分患者（23.0%至62.4%）的HbA1c水平甚至达到了非糖尿病范围（<5.7%）13。
  • 减重效果： 除了出色的降糖作用，替尔泊肽在2型糖尿病患者中也带来了显著的体重减轻。在SURPASS研究中，替尔泊肽治疗组患者的平均体重减轻了5.4 kg至11.7 kg，其中20.7%至68.4%的患者体重减轻超过10%13。
  • 心血管安全性： 尽管替尔泊肽的心血管安全性评估尚未完全结束，但其在临床试验项目中的MACE-4（非致死性心肌梗死、非致死性卒中、心血管死亡和因心绞痛住院）事件发生率倾向于降低，并且所有分析的心血管事件的风险比均未高于1.0，符合心血管安全性的传统定义13。一项正在进行中的SURPASS-CVOT试验旨在提供替尔泊肽与度拉鲁肽相比在心血管结局方面的确切证据，该试验招募了大量伴有动脉粥样硬化性心血管疾病的2型糖尿病患者，预计将进一步明确替尔泊肽的心血管保护作用3839。初步结果显示，替尔泊肽在主要心血管事件（MACE）复合终点上，与度拉鲁肽相比表现出非劣效性39。

肥胖症减重领域（SURMOUNT项目）：
SURMOUNT系列临床试验主要评估替尔泊肽在非糖尿病肥胖或超重患者中的减重疗效。

  • 显著的体重减轻： SURMOUNT-1研究是一项针对肥胖或超重成年人的III期临床试验，结果显示，在72周治疗后，替尔泊肽5 mg、10 mg和15 mg剂量组的平均体重百分比变化分别为-15.0%、-19.5%和-20.9%，而安慰剂组为-3.1%40。在10 mg和15 mg剂量组中，分别有50%和57%的患者体重减轻超过20%40。在中国人群中的SURMOUNT-CN研究也获得了相似的结果，52周后替尔泊肽10 mg和15 mg剂量组分别实现了-13.6%和-17.5%的平均体重减轻41。
  • 长期体重维持： SURMOUNT-4研究评估了替尔泊肽对体重减轻维持的影响。在36周的开放标签导入期后，患者平均体重减轻20.9%。随后随机分组，继续使用替尔泊肽的患者在52周内进一步减轻了5.5%的体重，而转用安慰剂的患者则体重反弹了14.0%42。这表明持续的替尔泊肽治疗对于维持和增强初始体重减轻至关重要42。
  • 新适应症的拓展： 替尔泊肽在代谢功能障碍相关脂肪性肝炎（MASH）43和阻塞性睡眠呼吸暂停（OSA）44等肥胖相关并发症的治疗中也展现出潜力。SURMOUNT-OSA研究表明，替尔泊肽能显著降低阻塞性睡眠呼吸暂停患者的呼吸暂停低通气指数（AHI），改善体重、缺氧负荷和睡眠相关结局44。

与司美格鲁肽的头对头试验疗效对比：
尽管目前尚无直接比较司美格鲁肽2.4 mg（减重剂量）与替尔泊肽（减重剂量）在同一临床试验中的头对头数据，但多项网络荟萃分析和间接比较研究提供了重要的线索。

  • 降糖方面： 一项针对2型糖尿病患者的系统综述和网络荟萃分析显示，替尔泊肽在降低HbA1c方面优于司美格鲁肽。与司美格鲁肽2.0 mg相比，替尔泊肽15 mg、10 mg和5 mg在HbA1c降低方面表现出可比或更优的疗效。特别是在体重减轻方面，替尔泊肽所有剂量均比司美格鲁肽2.0 mg更有效45。
  • 减重方面： 对于非糖尿病肥胖患者，多项分析表明替尔泊肽的减重效果通常优于司美格鲁肽。一项网络荟萃分析指出，替尔泊肽10 mg和15 mg的减重效果优于司美格鲁肽2.4 mg、利拉鲁肽3 mg等其他GLP-1RA46。另一项网络荟萃分析进一步确认，替尔泊肽（15 mg或10 mg）在减少体重和腰围方面优于司美格鲁肽（2.4 mg）和利拉鲁肽（3.0 mg）等其他GLP-1受体激动剂和多靶点激动剂47。近期，一项SURMOUNT-5的IIIb期临床试验直接比较了替尔泊肽（最高15mg）和司美格鲁肽（最高2.4mg）在非糖尿病肥胖症患者中的减重效果，结果显示，替尔泊肽组在72周时平均体重减轻20.2%，而司美格鲁肽组为13.7%，替尔泊肽在减重效果上显著优于司美格鲁肽48。
  • 安全性： 替尔泊肽和司美格鲁肽都具有类似的胃肠道不良反应谱，如恶心、呕吐、腹泻和便秘，这些不良反应通常为轻中度且主要发生在剂量递增期间134045。虽然替尔泊肽在更高剂量下可能会有更高比例的胃肠道事件发生，但通常是可耐受的，并且导致停药的事件较少4041。

总体而言，替尔泊肽作为GIP/GLP-1双受体激动剂，在降糖和减重方面展现出比单一GLP-1受体激动剂司美格鲁肽更强的临床疗效，尤其是在体重减轻方面具有显著优势。

2.3 口服GLP-1类药物的研发进展

口服GLP-1类药物的研发是该领域的重要趋势，旨在克服注射剂型给药不便的问题，提高患者依从性。目前，已有一款口服司美格鲁肽（oral semaglutide）获批上市，同时也有其他口服GLP-1类药物和递送技术处于不同研发阶段 49。

已上市口服GLP-1类药物：口服司美格鲁肽（Rybelsus）
口服司美格鲁肽是首个也是目前唯一一款获批上市的口服GLP-1受体激动剂，用于治疗2型糖尿病。

  • 技术路线： 口服司美格鲁肽的成功得益于其独特的制剂技术——与吸收增强剂水杨酸钠（SNAC）共配方。SNAC通过局部增加胃的pH值和保护司美格鲁肽免受胃蛋白酶降解，同时增强药物在胃黏膜的吸收，从而使其能够口服吸收 325051。
  • 生物利用度表现： 口服司美格鲁肽的生物利用度相对较低。在推荐的给药条件下（餐前30分钟空腹服用，水量不超过120 mL），其口服生物利用度约为0.8% 50。尽管生物利用度不高，但由于司美格鲁肽的半衰期长（约一周），每日一次给药仍能达到稳态血药浓度并发挥药效。值得注意的是，口服生物利用度的个体差异较大，稳态下的个体差异为33% 50。
  • 疗效： PIONEER III期临床试验项目证实了口服司美格鲁肽在2型糖尿病患者中的降糖和减重效果。每日一次口服14 mg司美格鲁肽可使HbA1c降低1.0%-1.4%，降糖效果显著优于西格列汀或恩格列净，并与利拉鲁肽相当 3252。在体重方面，口服司美格鲁肽的减重效果优于西格列汀和利拉鲁肽，与恩格列净相似 32。
  • 依从性： 相较于注射剂型，口服给药极大地提升了患者的便利性和依从性。尽管需要遵循严格的服药指导（如空腹、限制饮水量等），但口服途径对许多患者来说仍是更可接受的选择 3251。
  • 安全性： 口服司美格鲁肽的安全性谱与注射剂型相似，主要副作用是胃肠道不适，如恶心、呕吐、腹泻和便秘，这些反应通常是轻度至中度，并随时间推移而减轻 51。

在研口服GLP-1类药物及技术进展：
除了已上市的口服司美格鲁肽，全球范围内有多个口服GLP-1类药物处于不同研发阶段，主要的技术路线包括：

  1. 新型吸收增强剂： 类似SNAC的吸收增强剂仍在不断开发，以期进一步提高生物利用度，减少给药限制。例如，诺和诺德正在开发第二代（2G）口服司美格鲁肽，其新的配方在生物等效性研究中显示出与第一代口服司美格鲁肽相当的生物利用度，且没有增加新的安全担忧 53。
  2. 肽类纳米载体递送系统： 纳米技术被广泛应用于口服肽类药物的递送。例如，有研究开发出基于脂质纳米胶囊的系统，可提高GLP-1类似物艾塞那肽的口服生物利用度至4% 54。另一种利用聚合物（如壳聚糖、聚-N-(2-羟丙基)甲基丙烯酰胺）或玉米醇溶蛋白（zein）制备的纳米颗粒，也显示出通过保护肽类药物免受酶降解、促进肠道吸收，从而提高口服生物利用度的潜力 5556。这些纳米颗粒通常能延长药物在胃肠道的滞留时间，并增加GLP-1的分泌 5556。
  3. 非肽类小分子GLP-1受体激动剂： 多个公司正在开发非肽类小分子GLP-1受体激动剂，这些药物有望通过传统口服途径实现更好的吸收和生物利用度，从而简化给药条件并降低生产成本。一些非肽类小分子GLP-1激动剂正处于临床前或早期临床开发阶段 49。

口服剂型与注射剂型的疗效、依从性差异：

  • 疗效：
    • 降糖： 口服司美格鲁肽在2型糖尿病患者中的降糖效果与注射司美格鲁肽（SUSTAIN项目中的1.0 mg剂量）相当，均能显著降低HbA1c 32。
    • 减重： 注射司美格鲁肽2.4 mg每周一次可导致12-15%的体重减轻 49，而口服司美格鲁肽的减重效果虽然优于西格列汀和利拉鲁肽，但与注射剂型相比通常稍弱 32。
  • 依从性：
    • 口服剂型显著提高了患者的依从性和生活质量。许多患者对每日口服药片的接受度高于每周或每日注射。然而，口服司美格鲁肽严格的给药限制（空腹、少量水、餐前固定时间）可能会对部分患者的依从性造成一定影响。
    • 注射剂型尽管存在针头恐惧和给药不便，但由于其长效（每周一次）和相对稳定的药物吸收，对于习惯注射的患者来说，依从性也较好。

未来展望：
口服GLP-1类药物的研发为糖尿病和肥胖症患者提供了更多治疗选择，特别是对于那些不愿或不适合注射治疗的患者。随着新一代口服递送技术和非肽类小分子GLP-1激动剂的不断突破，口服GLP-1类药物的生物利用度、疗效和依从性有望进一步提升，使其在未来市场中扮演更重要的角色。

3. GLP-1类联合疗法的研究进展

3.1 现有联合治疗方案的临床疗效

GLP-1类药物凭借其独特的降糖、减重和心血管保护等多重益处，已成为2型糖尿病和肥胖症管理的重要基石。为了进一步优化治疗效果，减少并发症风险，并应对疾病的复杂性，将GLP-1类药物与其他作用机制不同的药物联合应用已成为重要的研究方向和临床实践。当前主要的联合治疗方案包括与二甲双胍、SGLT-2抑制剂等传统降糖药物的联用，以及与其他减重靶点药物的联用。

3.1.1 GLP-1类药物与二甲双胍的联合治疗

二甲双胍是2型糖尿病的一线治疗药物，其作用机制主要是通过抑制肝糖原输出、增加外周组织对葡萄糖的摄取和利用。GLP-1类药物与二甲双胍联合使用具有良好的协同效应：

  • 疗效叠加： 两者通过不同机制协同降糖，能够更有效地降低HbA1c水平，尤其适用于二甲双胍单药治疗血糖控制不佳的患者。
  • 减重协同： GLP-1类药物的减重作用与二甲双胍对体重的中性或轻微减轻作用相结合，有助于更好地管理患者体重。
  • 安全性与耐受性： 尽管GLP-1类药物可能引起胃肠道不适，但与二甲双胍联合时，通常不会显著增加不良反应的发生率，且长期使用的安全性良好。

3.1.2 GLP-1类药物与SGLT-2抑制剂的联合治疗

GLP-1受体激动剂和钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂是两种在心血管和肾脏保护方面均显示出显著益处的新型降糖药物。两者的联合应用备受关注，并已有多项临床研究证实其协同增效作用 5758。

  • 协同降糖： SGLT-2抑制剂通过促进尿糖排泄来降低血糖，而GLP-1类药物则通过促进胰岛素分泌、抑制胰高糖素分泌、延缓胃排空和抑制食欲来发挥作用。这两种机制的结合可带来更强效的血糖控制，且低血糖风险低 58。
  • 心血管和肾脏保护： 独立研究已证实GLP-1受体激动剂和SGLT-2抑制剂均能显著降低2型糖尿病患者的心血管事件风险和延缓慢性肾病进展 5758。一项系统综述和荟萃分析表明，GLP-1受体激动剂的心血管和肾脏益处不受SGLT-2抑制剂使用的影响，无论患者是否基线使用SGLT-2抑制剂，GLP-1受体激动剂均能降低主要不良心血管事件（MACE）风险21% 59。此外，SGLT-2抑制剂与GLP-1受体激动剂的联合使用与MACE风险降低30%和严重肾脏事件风险降低57%相关，优于单一用药 60。这表明两者可能通过不同的途径提供保护作用，从而实现互补和叠加效应 58。
  • 体重管理： SGLT-2抑制剂通过促进尿糖排泄可带来适度体重减轻，与GLP-1类药物强大的减重效果相结合，能够更好地管理超重和肥胖的糖尿病患者。
  • 临床试验数据： SUSTAIN 9研究显示，在SGLT-2抑制剂治疗基础上加用司美格鲁肽1.0 mg每周一次，能进一步显著降低HbA1c（估计治疗差异为-1.42%）和体重（估计治疗差异为-3.81 kg），且安全性良好 61。FLOW试验的亚组分析也发现，无论患者是否使用SGLT-2抑制剂，司美格鲁肽对肾脏结局的益处是一致的，且对主要心血管事件和全因死亡的益处不受SGLT-2抑制剂使用的影响 62。口服司美格鲁肽在SOUL试验中也显示出独立于SGLT-2抑制剂使用的心血管益处 63。

3.1.3 GLP-1类药物与二肽基肽酶-4（DPP-4）抑制剂的联合治疗

DPP-4抑制剂通过抑制内源性GLP-1的降解来提高其水平，从而发挥降糖作用。理论上，GLP-1受体激动剂与DPP-4抑制剂的联用可能存在重叠，但部分研究探讨了这种联合的可能性。然而，由于两者作用机制存在一定相似性，目前通常不推荐将GLP-1受体激动剂与DPP-4抑制剂联合使用作为首选方案，以免增加不良反应而无明显额外获益。

3.1.4 GLP-1类药物与其他减重靶点药物的联合治疗

鉴于肥胖症的复杂性，针对不同机制的药物联合应用有望实现更显著的减重效果。

  • GLP-1与胰淀素（Amylin）类似物： 胰淀素是一种与GLP-1共同分泌的肠道激素，具有抑制胰高糖素分泌、延缓胃排空和增加饱腹感的作用。卡格林肽（Cagrilintide）是长效胰淀素类似物，与司美格鲁肽2.4 mg联用可实现更显著的体重减轻。一项Ib期临床试验显示，卡格林肽与司美格鲁肽2.4 mg联用，能带来高达17.1%的平均体重减轻，高于单一司美格鲁肽的减重效果 6465。
  • GLP-1与纤维母细胞生长因子21（FGF21）类似物： FGF21是一种具有改善脂质代谢、胰岛素敏感性和肝脏脂肪变性等多种代谢益处的激素。FGF21类似物与GLP-1受体激动剂的联合治疗被认为可以协同增效，特别是在改善血脂异常（尤其是高甘油三酯血症）和肝脏脂肪变性方面 6667。
  • 多靶点激动剂： 替尔泊肽作为GIP/GLP-1双靶点激动剂，本身就是一种联合疗法，其强大的减重和降糖效果已证明了多靶点策略的优势 68。未来，将GLP-1、GIP、胰高糖素（Glucagon）等多种肠促胰素或代谢激素组合的三靶点激动剂（如Retatrutide）也正在开发中，有望实现更接近减重手术的疗效 64。

3.1.5 受益人群

GLP-1类联合治疗方案的受益人群广泛，主要包括：

  • 血糖控制不佳且伴有心血管或肾脏并发症的2型糖尿病患者： GLP-1受体激动剂被证明对这类患者具有肾脏保护作用 69。
  • 伴有超重或肥胖的2型糖尿病患者： 联合治疗可实现更显著的体重减轻和代谢改善，有助于降低肥胖相关风险。
  • 单纯肥胖且伴有代谢综合征的患者： 特别是那些对单一GLP-1类药物减重效果不满意，或希望达到更大减重幅度的患者，可以考虑更强效的多靶点联合方案。
  • 非酒精性脂肪肝病（NAFLD）/代谢功能障碍相关脂肪性肝病（MASLD）患者： GLP-1类药物本身对NAFLD/MASLD有益 66。
  • 多囊卵巢综合征（PCOS）患者： GLP-1受体激动剂（如利拉鲁肽）单独或与二甲双胍联合已被研究用于治疗肥胖型PCOS患者，可显著减轻体重和降低睾酮水平，对胰岛素抵抗的改善也显示出混合结果 7071。未来，更强效的联合疗法可能为这类患者带来更多益处。

3.2 固定复方制剂的研发布局

随着对GLP-1类药物及其多重生理作用机制的深入理解，药物研发正从单一靶点激动剂向多靶点激动剂，乃至固定复方制剂发展，以期实现更强的疗效和更全面的代谢改善。这些复方制剂通常旨在通过单一药物同时激活多个肠促胰素受体，或将GLP-1受体激动剂与具有互补作用机制的其他活性成分结合。

当前在研的GLP-1类多靶点复方制剂

  1. GIP/GLP-1双靶点激动剂（如替尔泊肽）：
    替尔泊肽（Tirzepatide）已获批上市，是目前最成功的双靶点激动剂，其通过同时激活GIP和GLP-1受体，在降糖和减重方面均展现出超越单一GLP-1受体激动剂的疗效 4972。其临床研究（SURPASS和SURMOUNT系列）已充分证明其在2型糖尿病和肥胖症治疗中的卓越表现。

  2. GLP-1/胰高糖素双靶点激动剂（如Mazdutide, Suvodutide）：
    这类药物旨在结合GLP-1的降糖和减重作用与胰高糖素（Glucagon）的能量消耗和脂肪肝改善作用。胰高糖素激动剂可以增加能量消耗，并可能改善肝脏脂肪变性，使其成为治疗肥胖和非酒精性脂肪性脂肪肝病（NAFLD）/代谢功能障碍相关脂肪性肝病（MASLD）的有前景靶点 4973。

    • Mazdutide (IBI362): 由信达生物和礼来合作开发，是GLP-1R/GCGR（胰高糖素受体）双重激动剂。临床试验显示，Mazdutide在减重和改善代谢指标方面表现出色。参考文献[3]指出，一项针对中国肥胖患者的II期临床研究发现，高剂量Mazdutide组患者的体重减轻显著 74。
    • Suvodutide (BI 456906): 勃林格殷格翰和Zealand Pharma合作开发的GLP-1R/GCGR双重激动剂，已进入III期临床试验，主要用于治疗肥胖症和MASLD 74。早期数据表明其具有显著的减重效果和肝脏脂肪改善作用。

  3. GLP-1/GIP/胰高糖素三靶点激动剂（如Retatrutide）：
    这类“三靶点”激动剂代表了多靶点策略的最新进展，旨在同时激活GLP-1、GIP和胰高糖素受体，以期实现最强的体重减轻和代谢改善效果 497375。

    • Retatrutide (LY3437943): 礼来公司开发的三靶点激动剂，在II期临床试验中展现了惊人的减重效果。在肥胖患者中，最高剂量（12 mg）治疗48周后，平均体重减轻高达24.2% 74。这使得Retatrutide的减重效果有望超越替尔泊肽，甚至接近减重手术的效果。Retatrutide已进入III期临床试验，有望成为下一代超高效减重药物。

  4. GLP-1/胰淀素（Amylin）受体激动剂（如Cagrisema）：
    这种组合旨在结合GLP-1的降糖减重作用与胰淀素的饱腹感增强、胃排空延缓和胰高糖素抑制作用 497275。

    • Cagrisema (Cagrilintide + Semaglutide): 诺和诺德正在开发的固定复方制剂，由长效胰淀素类似物Cagrilintide和GLP-1受体激动剂司美格鲁肽组成。在II期临床试验中，Cagrisema显示出比单一司美格鲁肽更强的减重效果，在肥胖患者中可实现高达17.1%的平均体重减轻 74。该复方已进入III期临床试验。

复方制剂相对于单药联合使用的临床优势

固定复方制剂与分别使用两种或多种单一药物相比，具有以下潜在优势：

  1. 更强的协同效应和疗效提升： 多靶点激动剂通过同时作用于多个生理通路，可以产生超越单一药物的协同效应。例如，替尔泊肽结合了GIP和GLP-1的双重益处，而三靶点激动剂更是旨在实现对代谢通路的全面调控。这种协同作用不仅体现在降糖和减重幅度上，还可能在改善胰岛素敏感性、肝脏脂肪变性、心血管风险等多个方面产生更显著的益处 76。
  2. 更高的患者依从性： 固定复方制剂通常意味着患者只需使用一个药物，而不是同时服用多种药物。这简化了治疗方案，减少了给药次数和药物管理负担，从而有望显著提高患者的治疗依从性，尤其是对于需要长期治疗的慢性疾病如2型糖尿病和肥胖症 77。
  3. 潜在的安全性优势： 通过将不同机制的药物结合在一个制剂中，研究人员可以优化各成分的比例，以在不显著增加不良反应的前提下，最大限度地发挥协同作用。有时，组合疗法甚至可以降低某些单一药物高剂量使用时可能出现的副作用。例如，通过激活多个受体，可能不需要将单个激动剂的剂量提升到非常高的水平来达到期望的疗效，从而减少单一靶点高激动可能带来的不良反应。
  4. 便利的剂量调整和管理： 固定复方制剂简化了临床医生对药物的剂量调整和管理。在需要调整治疗时，通常只需调整复方制剂的剂量，而无需分别调整多个药物，从而降低了治疗复杂性。
  5. 药学经济学效益： 尽管开发成本可能较高，但从长远来看，成功的固定复方制剂可能通过提高疗效、改善依从性、减少并发症和住院率，从而降低总体医疗成本。

然而，固定复方制剂的研发也面临挑战，包括如何平衡不同靶点的激动强度、确保各成分的药代动力学匹配以及评估其长期安全性和成本效益。尽管如此，鉴于其在疗效和依从性方面的巨大潜力，多靶点固定复方制剂无疑代表了GLP-1类药物未来研发的重要方向。

4. 安全性与停药反弹问题的研究进展

4.1 安全性研究数据汇总

GLP-1类药物在治疗2型糖尿病和肥胖症方面取得了显著进展，但其安全性，特别是长期使用的潜在风险，一直是临床和研究关注的重点。以下将汇总GLP-1类药物常见的胃肠道不良反应、严重的胰腺/肝胆不良反应，以及长期使用可能涉及的心血管和肿瘤风险的最新研究结论。

4.1.1 常见胃肠道不良反应

GLP-1类药物最常见的副作用是胃肠道不适，这与它们延缓胃排空、抑制食欲等作用机制密切相关 7879。

  • 恶心、呕吐、腹泻和便秘： 这些是报告最多的不良事件，发生率通常高于安慰剂组。例如，司美格鲁肽相关的临床试验显示，恶心、便秘和呕吐的发生率高于安慰剂组 80。一项关于司美格鲁肽安全性的综述指出，恶心、呕吐和腹泻的发生率分别为42%、15%和22%左右 81。利拉鲁肽的临床研究中也观察到类似的胃肠道反应，如腹泻（38%）、便秘（27%）和食欲不振（31%） 82。
  • 程度与持续时间： 这些胃肠道反应通常是轻度至中度的，并且呈一过性，主要发生在治疗初期和剂量递增阶段。随着治疗的进行，大部分患者的症状会逐渐减轻或消失 7981。
  • 与剂量相关性： 胃肠道不良反应的发生率和严重程度通常与药物剂量呈正相关。例如，司美格鲁肽0.4 mg组的恶心发生率为42%，远高于安慰剂组的11%，且便秘和呕吐的发生率也高于安慰剂组，这表明较高剂量的药物可能会导致更高比例的胃肠道事件，也可能导致更高的停药率 80。
  • 应对策略： 为了提高患者耐受性，临床上通常采用小剂量起始、缓慢递增（剂量滴定）的策略。

4.1.2 严重的胰腺/肝胆不良反应

关于GLP-1类药物与胰腺炎、胰腺癌以及胆囊疾病的关系，一直是安全性评估的重要组成部分。

  • 胰腺炎： 尽管早期研究和动物模型曾引发对GLP-1类药物可能增加胰腺炎风险的担忧，但多项大型临床试验和真实世界数据分析并未发现GLP-1受体激动剂与急性胰腺炎之间存在明确的因果关系 8183。在对司美格鲁肽的安全性评估中，也未发现其会增加胰腺炎的发生风险 81。
  • 胰腺癌： 同样，关于GLP-1类药物与胰腺癌风险增加的担忧也未得到充分证实。由于胰腺癌发病率较低，且其自然病程较长，目前的临床试验随访时间可能不足以得出明确结论。然而，现有数据显示，尚无证据表明GLP-1受体激动剂会增加胰腺癌风险 81。
  • 胆囊疾病（胆石症、胆囊炎）： GLP-1类药物，尤其是司美格鲁肽，已被证实会增加胆道疾病（如胆石症）的风险 81。这可能与药物导致的体重快速下降以及对胆囊收缩功能的影响有关。一项关于司美格鲁肽安全性的综述指出，与安慰剂相比，司美格鲁肽可能会增加胆道疾病的风险。因此，在使用GLP-1类药物治疗期间，尤其是对于体重快速下降的患者，需注意监测胆囊相关症状。

4.1.3 长期使用心血管和肿瘤风险相关的最新研究结论

  • 心血管风险： GLP-1类药物在心血管安全性方面表现出色，多项心血管结局试验（CVOTs）证实了其心血管保护作用。

    • 心血管获益： GLP-1受体激动剂已被证明能够降低2型糖尿病患者主要不良心血管事件（MACE）的风险，包括心血管死亡、非致死性心肌梗死和非致死性卒中 78。一项大型回顾性队列研究发现，GLP-1受体激动剂与全因死亡率显著降低相关，并能降低缺血性心脏病、心力衰竭、心律失常、高血压、卒中和房颤等多种心血管并发症的风险 30。
    • 糖尿病视网膜病变： 早期有研究提示GLP-1受体激动剂在某些情况下可能与糖尿病视网膜病变恶化有关，尤其是在血糖快速下降的患者中 81。然而，对于这种关联是否是类效应或特定药物效应，以及其临床意义，仍需更多研究。
    • 新生血管性年龄相关性黄斑变性（nAMD）： 一项回顾性队列研究发现，糖尿病患者使用GLP-1受体激动剂可能与nAMD风险增加2倍有关 84。这提示需要进一步研究来阐明其病理生理机制，并权衡GLP-1类药物的益处与风险。

  • 肿瘤风险： 关于GLP-1类药物与肿瘤风险的关联，尤其是甲状腺髓样癌，曾是早期关注的焦点。

    • 甲状腺髓样癌： 在啮齿类动物研究中，GLP-1受体激动剂曾显示出与甲状腺C细胞增生和甲状腺髓样癌的关联。然而，在人体研究中，尚无确凿证据表明GLP-1受体激动剂会增加甲状腺髓样癌的风险 8183。由于这种癌症的罕见性，需要更长时间和更大规模的随访研究来得出最终结论。
    • 其他癌症：
      • 一项针对肥胖成年人的回顾性队列研究显示，使用GLP-1受体激动剂与整体癌症风险降低有关（风险比0.83），特别是子宫内膜癌（HR 0.75）、卵巢癌（HR 0.53）和脑膜瘤（HR 0.69）的风险降低 85。
      • 然而，该研究也指出GLP-1受体激动剂可能与肾癌风险略微增加相关（HR 1.38），但这需要更长期的随访来明确其潜在机制和临床意义 85。
      • 另一项药物靶点孟德尔随机化和临床试验的证据显示，GLP-1受体激动剂可能降低乳腺癌和基底细胞癌的风险，但可能增加结直肠癌的风险 86。
      • 需要强调的是，肿瘤研究往往需要较长的观察期，目前大部分临床试验的随访时间相对有限，难以捕捉所有潜在的长期肿瘤风险。

总而言之，GLP-1类药物具有总体良好的风险/效益比 81。常见的胃肠道不良反应通常是轻度且可管理的。在心血管方面具有显著的保护作用。胰腺和甲状腺癌的风险目前未得到证实。然而，对于胆道疾病、糖尿病视网膜病变和新生血管性年龄相关性黄斑变性，以及某些特定癌症（如肾癌和结直肠癌）的潜在风险，仍需持续监测和更深入的长期研究。

4.2 停药后反弹特征与干预研究

GLP-1类药物在减重和血糖控制方面的显著疗效，使得其停药后的效果持续性成为一个重要的临床问题。多项研究表明，停用GLP-1类药物后，患者的体重和血糖水平常会出现一定程度的反弹，这提示肥胖和2型糖尿病作为慢性疾病，需要长期管理 7887。

4.2.1 停药后体重反弹的特征与影响因素

GLP-1类药物停药后的体重反弹现象在临床试验中已被广泛观察到：

  • 反弹幅度： 停药后的体重反弹幅度通常与治疗期间的减重幅度成正比 88。研究显示，停止利拉鲁肽治疗的患者体重平均反弹2.20 kg，而停止司美格鲁肽/替尔泊肽治疗的患者体重平均反弹9.69 kg 88。在司美格鲁肽治疗肥胖的STEP 4研究中，患者在停药一年内体重平均增加了6.9% 87。替尔泊肽治疗肥胖的SURMOUNT-4研究也显示，患者在停药后体重显著回升，而持续用药组体重则继续减轻 87。一项系统性回顾和荟萃分析指出，GLP-1受体激动剂停药后，体重平均反弹4.13 kg，BMI平均反弹0.84 kg/m²，腰围平均反弹3.64 cm 89。
  • 反弹速度： 体重反弹通常在停药后一年内迅速发生 87。这种快速的体重回升被认为是疾病复发，而非治疗失败，强化了肥胖作为一种慢性、易复发疾病的认知 87。
  • 生理学机制： 停药后的体重反弹可能与以下生理学机制有关 8790：
    1. 饥饿感增加与饱腹感降低： GLP-1类药物通过抑制食欲和增强饱腹感发挥减重作用，停药后这些作用消失，导致食欲恢复甚至增强，食物摄入量增加 90。
    2. 能量消耗减少： 减重本身会导致基础代谢率下降，停药后，身体可能倾向于恢复到治疗前的体重设定点（set point），重新启动体重防御机制，进一步促进体重回升 8790。
    3. 内分泌失衡： 停药可能导致瘦素、胃饥饿素等多种食欲调节激素水平失衡，促进体重增加 90。
    4. 肌肉量流失： 在减重过程中，除了脂肪量减少外，也可能伴随部分肌肉量的流失。停药后体重的反弹主要表现为脂肪量的优先恢复，导致肌少症性肥胖（sarcopenic obesity）的风险增加 87。
  • 影响因素：
    • 原始减重幅度： 减重幅度越大，停药后反弹的绝对体重可能也越大 8891。
    • 生活方式干预： 停用GLP-1RA治疗后会导致体重反弹，无论是否进行生活方式干预 88。
    • 患者依从性： 经济原因、副作用、注射恐惧或认为药物无效等都可能导致患者停药，进而引发体重反弹 9293。

4.2.2 停药后血糖回升的特征与影响因素

对于2型糖尿病患者，停用GLP-1类药物后，血糖水平也会出现反弹：

  • HbA1c回升： 停药后，患者的糖化血红蛋白（HbA1c）水平会显著回升。一项荟萃分析显示，停用GLP-1受体激动剂后，HbA1c平均反弹0.69% 89。
  • 并发症风险： 血糖控制不佳可能导致糖尿病相关并发症（如心血管事件、肾病进展）的风险再次升高。
  • 妊娠期影响： 对于在孕前或孕早期停用GLP-1类药物的女性，可能会面临更高的妊娠期体重增加、早产、妊娠期糖尿病和妊娠期高血压疾病的风险 94。

4.2.3 缓解停药反弹的干预策略研究进展

鉴于GLP-1类药物停药后体重和血糖反弹的普遍性，研究人员正在探索多种策略来缓解这一问题，以实现长期、可持续的治疗效果：

  1. 长期维持治疗：
    • 慢性病管理理念： 多数观点认为，肥胖和2型糖尿病是慢性、复发性疾病，需要像高血压和高血脂一样进行长期甚至终身治疗 878891。持续使用GLP-1类药物被认为是维持减重效果和心血管代谢益处的最佳策略 89。
    • SURMOUNT-4研究： 该研究明确证实，持续的替尔泊肽治疗对于维持和增强初始体重减轻至关重要。与转为安慰剂的患者相比，持续接受替尔泊肽治疗的患者体重得到了更好的维持和进一步减轻。
  2. 结构性减量或序贯治疗：
    • 剂量滴定或逐渐减量： 某些研究者提出，在计划停药时，可以考虑结构性地逐渐减少药物剂量（tapering approaches），而不是骤然停药，以帮助身体适应并可能减少反弹 87。
    • 序贯其他药物： 在停用高强度GLP-1类药物后，可以考虑序贯其他具有减重或降糖效果的药物，例如SGLT-2抑制剂或二甲双胍，以维持部分疗效。
  3. 强化生活方式干预：
    • 饮食管理： 持续进行健康的饮食管理，包括控制热量摄入、均衡营养，是减重维持的基础。
    • 运动干预： 规律的体育锻炼，特别是抗阻训练，有助于增加和维持肌肉量，对抗因减重或停药导致的肌肉流失，从而改善身体成分和代谢健康 87。研究显示，力量训练可以抵消或减少与停药相关的肌肉量流失 87。
    1. 行为疗法与心理支持： 结合行为疗法、心理咨询和社群支持，可以帮助患者建立健康的饮食和运动习惯，应对情绪性进食，从而更好地维持体重。
  4. 探索新的治疗组合：
    • 多靶点激动剂： 替尔泊肽等双靶点甚至三靶点激动剂，由于其更强的减重和代谢改善效果，可能在停药后提供更长的“保护期”或更小的反弹幅度。
    • 与其他减重机制药物联用： 例如，将GLP-1类药物与具有不同作用机制的减重药物联合使用，以期达到更持久的减重效果。
  5. 生物标志物研究：
    • 识别反弹高风险人群： 识别与体重反弹相关的生物标志物，可以帮助临床医生在治疗前评估患者的风险，并制定更个性化的干预方案。
  6. 非代谢类适应症的拓展：
    • 值得关注的是，GLP-1类药物除了代谢作用，还在神经精神疾病领域展现出潜力。例如，艾塞那肽可增强GLP-1信号通路并减轻海洛因戒断小鼠的焦虑样行为，提示GLP-1受体可能成为调节情绪状态的分子靶点，为预防阿片类药物复发提供经验支持 95。此外，GLP-1受体激动剂杜拉鲁肽正在研究用于戒烟，可能通过减轻尼古丁戒断症状和减少戒烟后体重增加来提高戒烟成功率 96。这些非代谢类适应症的探索可能会为GLP-1类药物提供更广泛的临床应用前景，并可能改变停药反弹的临床意义。

总而言之，GLP-1类药物停药后的体重和血糖反弹是一个普遍存在的挑战。临床实践应强调长期维持治疗的重要性，并结合生活方式干预、结构性减量和序贯治疗等多种策略，以最大化患者的长期获益。

5. GLP-1类药物产业竞争格局分析

5.1 全球市场竞争格局

GLP-1类药物在全球糖尿病和肥胖症治疗市场中占据着举足轻重的地位，并且市场规模正以惊人的速度扩张。得益于其卓越的疗效和心血管代谢获益，该类药物已成为跨国药企竞相投入研发和市场推广的焦点领域。

已上市GLP-1类药物的适应症覆盖与市场表现

目前，全球市场上主要的GLP-1类药物包括诺和诺德的利拉鲁肽（Liraglutide）和司美格鲁肽（Semaglutide），以及礼来的度拉鲁肽（Dulaglutide）和替尔泊肽（Tirzepatide）。这些药物的适应症已从最初的2型糖尿病扩展至肥胖症、心血管疾病风险管理等多个领域，极大地拓宽了市场空间。

  1. 诺和诺德（Novo Nordisk）：

    • 利拉鲁肽（Liraglutide，商品名：Victoza/Saxenda）：作为每日注射一次的GLP-1受体激动剂，利拉鲁肽是首批被批准用于2型糖尿病和肥胖症治疗的GLP-1类药物之一。其在糖尿病治疗中的领先地位使其获得了可观的市场份额。Saxenda作为其减重适应症的品牌，也为诺和诺德在肥胖管理领域奠定了基础。
    • 司美格鲁肽（Semaglutide，商品名：Ozempic/Wegovy/Rybelsus）：司美格鲁肽是诺和诺德的“拳头产品”，以其每周一次的皮下注射剂型（Ozempic，用于2型糖尿病；Wegovy，用于肥胖症）和每日一次的口服剂型（Rybelsus，用于2型糖尿病）横扫市场。
      • Ozempic在2型糖尿病市场表现强劲，其优异的降糖、减重和心血管获益使其成为许多患者和医生的首选。
      • Wegovy作为首个获批用于单纯肥胖症的GLP-1受体激动剂，在全球范围内引发了巨大的市场需求，甚至一度出现供不应求的情况。其在临床试验中展现的显著减重效果（高达15-17%的体重减轻）使其成为肥胖症治疗的“颠覆者”。
      • Rybelsus作为首款口服GLP-1受体激动剂，为不愿或不便注射的患者提供了新的选择，进一步扩大了司美格鲁肽的市场渗透率。
    • 诺和诺德凭借司美格鲁肽系列产品，已成为GLP-1类药物市场的绝对领导者，其销售额持续飙升，推动公司市值屡创新高。

  2. 礼来（Eli Lilly and Company）：

    • 度拉鲁肽（Dulaglutide，商品名：Trulicity）：度拉鲁肽是每周注射一次的GLP-1受体激动剂，在司美格鲁肽之前一直是市场上的重要参与者。它也具有良好的降糖和心血管保护作用。
    • 替尔泊肽（Tirzepatide，商品名：Mounjaro/Zepbound）：替尔泊肽是首个GIP/GLP-1双受体激动剂，被认为是GLP-1类药物的“超级明星”。
      • Mounjaro于2022年获批用于2型糖尿病治疗，其在降低HbA1c和减轻体重方面的效果均优于单一GLP-1受体激动剂，包括司美格鲁肽 97。
      • Zepbound于2023年末获批用于肥胖症治疗，其在临床试验中展现的减重效果甚至超越了司美格鲁肽（最高剂量可达20%以上的体重减轻） 98。
    • 礼来凭借替尔泊肽的强大疗效，迅速在GLP-1市场占据了一席之地，并对诺和诺德的市场领导地位构成强劲挑战。

头部跨国药企的产品管线布局与竞争优势

头部跨国药企，特别是诺和诺德和礼来，在GLP-1类药物领域的竞争优势主要体现在以下几个方面：

  1. 强大的研发投入与创新能力：两家公司持续投入巨资进行GLP-1类药物的研发，不仅推动了单靶点、双靶点激动剂的创新，还在积极探索三靶点激动剂（如礼来的Retatrutide，同时激动GLP-1R、GIPR和GCGR）以及其他新型GLP-1类药物。例如，诺和诺德正在开发口服司美格鲁肽的第二代产品以及司美格鲁肽与胰淀素类似物（Cagrilintide）的固定复方制剂（Cagrisema），以进一步提升疗效和便利性。
  2. 丰富的适应症拓展：除了2型糖尿病和肥胖症，GLP-1类药物的适应症正在向非酒精性脂肪肝炎（NASH）、心力衰竭、阻塞性睡眠呼吸暂停、阿尔茨海默病甚至成瘾性疾病等领域拓展。这种多元化的适应症布局将为药物带来更广阔的市场空间。
  3. 完善的生产与供应链管理：面对GLP-1类药物日益增长的需求，具备稳定、高效的生产能力和全球供应链管理能力是确保市场供应的关键。诺和诺德和礼来都在积极扩大生产规模，以满足市场需求，但仍面临供不应求的挑战。
  4. 品牌效应与市场营销：作为行业领导者，诺和诺德和礼来在GLP-1类药物领域建立了强大的品牌效应和完善的市场营销网络。其广泛的临床试验数据、专业推广以及公众认知度，使其在新产品上市时能够迅速打开市场。
  5. 专利布局与市场独占期：药物专利是制药企业保护其研发投入和市场独占期的重要工具。GLP-1类药物的专利保护涵盖活性成分、制剂、给药装置等多个方面，确保了品牌药在一定时期内的市场独占地位。然而，专利到期后仿制药的进入将加剧市场竞争 99。

市场挑战与展望

尽管GLP-1类药物市场前景广阔，但也面临一些挑战：

  • 高昂的价格：GLP-1类药物的月治疗成本相对较高，无保险患者每月可能需支付892美元（司美格鲁肽）至1418美元（利拉鲁肽），这限制了其在全球范围内的可及性 98。尽管制造商会提供折扣，但净价格仍高达每月312至761美元 100。
  • 生物类似药的威胁：随着原研药专利的逐步到期，生物类似药的开发和上市将成为主要的竞争力量，可能会带来价格竞争和市场份额的再分配 98。
  • 新兴竞争者：除了诺和诺德和礼来，其他制药公司也在积极布局GLP-1类药物市场，例如辉瑞（Pfizer）的口服GLP-1类药物，以及众多生物科技公司在多靶点激动剂和口服制剂方面的探索，未来市场竞争将更加激烈。

总而言之，全球GLP-1类药物市场正处于高速增长期，由诺和诺德和礼来两大巨头主导。它们凭借深厚的研发实力、广泛的适应症布局和强大的市场推广能力，构建了显著的竞争优势。然而，高昂的价格、即将到来的专利悬崖以及新兴竞争者的涌入，将是未来几年影响市场格局的关键因素。

5.2 国内市场竞争态势

中国作为全球最大的糖尿病患者群体所在地和日益增长的肥胖人口市场，GLP-1类药物的市场潜力巨大。国内市场竞争格局复杂，既有跨国药企原研产品的领先，也有本土药企在仿制药和创新药领域的积极布局。

国内药企在GLP-1仿制药领域的研发进度

由于原研GLP-1类药物的专利保护，目前国内市场上的GLP-1类仿制药主要集中在较早上市的品种，如艾塞那肽（exenatide）和利拉鲁肽（liraglutide）。

  • 艾塞那肽仿制药： 艾塞那肽作为首个上市的GLP-1受体激动剂，其专利已逐步到期，国内多家药企已布局或上市了艾塞那肽的仿制药。例如，华东医药的利鲁平（艾塞那肽注射液）已于2017年获批上市，打破了外资企业在该领域的垄断，并通过集采迅速占据了一定市场份额。
  • 利拉鲁肽仿制药： 利拉鲁肽的全球专利保护也已接近尾声。国内药企如通化东宝、丽珠集团、翰宇药业、联邦制药等均已积极布局利拉鲁肽的生物类似药，部分已进入临床后期阶段或已提交上市申请。预计未来几年，随着利拉鲁肽仿制药的陆续上市，将进一步加剧市场竞争，并可能带动价格下降，提升药物可及性。

国内药企在创新GLP-1类药物领域的研发进度

除了仿制药，国内药企在GLP-1类创新药领域也表现出强劲的研发实力，聚焦于长效、多靶点、口服等方向。

  • 长效GLP-1受体激动剂： 多数国内药企的创新方向是开发每周一次甚至更长周期的GLP-1受体激动剂。例如，豪森药业的聚乙二醇洛塞那肽（PEG-Loxenatide）已获批上市，是国内首个自主研发的原创长效GLP-1受体激动剂，具有独特的分子结构和给药优势。恒瑞医药、信立泰等也在长效GLP-1赛道有所布局。
  • 多靶点激动剂： 礼来的替尔泊肽（GIP/GLP-1双靶点）在全球的成功，极大地激发了国内药企对多靶点药物的兴趣。
    • 信达生物的Mazdutide（IBI362）：这是一种GLP-1R/GCGR（胰高糖素受体）双重激动剂，已在中国提交上市申请，并于2025年6月获得批准，用于超重或肥胖成人体重管理以及2型糖尿病的血糖控制 101。Mazdutide的上市值得期待 101。
    • 华东医药的HDM1002：这是一款GIP/GLP-1双靶点激动剂，已进入临床I期。
    • 先为达生物的Fasiglifen（XW003）：这是一款GLP-1R/GIPR双靶点激动剂，也已进入临床试验阶段。
  • 口服GLP-1类药物： 借鉴诺和诺德口服司美格鲁肽的成功经验，国内药企也在积极探索口服剂型。目前主要通过两种路径：一是改进肽类药物的口服递送技术；二则是开发小分子GLP-1受体激动剂。华东医药、派格生物等公司均有口服GLP-1在研管线。

医保谈判、集采政策对国内市场竞争的影响

中国的医保谈判和药品集中采购（集采）政策对GLP-1类药物的市场格局产生了深远影响：

  • 价格大幅下降，提升可及性： GLP-1类药物进入医保目录后，通过国家医保谈判，价格通常会有较大幅度的下降。例如，诺和诺德的利拉鲁肽注射液（Victoza）和司美格鲁肽注射液（Ozempic）已通过医保谈判成功进入国家医保目录。这显著降低了患者的用药负担，使得更多患者能够负担得起这些创新药物，从而加速了市场渗透率的提升。
  • 仿制药的放量与市场重塑： 药品集采政策旨在通过量价挂钩的方式，以较低价格采购大量药品，推动仿制药替代原研药。对于已过专利期的GLP-1类药物，如艾塞那肽，仿制药通过集采快速放量，获得了巨大的市场份额，而原研药的市场份额则被大幅挤压。未来随着利拉鲁肽等更多GLP-1类药物专利到期和仿制药上市，集采将进一步重塑该类药物的市场格局。
  • 加速创新药研发： 医保谈判和集采虽然导致价格下降，但也促使本土药企加速创新研发，以期在差异化竞争中占据优势。对于未被纳入集采的创新药，如果其临床价值显著且具有独特的疗效优势，通过医保谈判仍可获得可观的市场空间。这鼓励了企业投入更多资源开发具有“同类最优”或“全新机制”的GLP-1类药物。
  • 市场集中度提高： 集采政策往往导致市场份额向少数中标企业集中，特别是具有成本优势和生产能力的企业。这可能会淘汰一部分竞争力较弱的企业，促使行业洗牌。

总体而言，国内GLP-1市场正处于快速发展和激烈竞争并存的阶段。跨国药企凭借原研创新和全球影响力保持领先，而国内药企则通过仿制和创新双轮驱动，力求在细分市场和未来竞争中占据一席之地。医保谈判和集采政策在提升药物可及性的同时，也加速了市场竞争和产业升级。

5.3 上游产业链竞争情况

GLP-1类药物的研发和生产是一个复杂而精密的系统工程，其上游产业链涉及原料药的生产、注射给药装置的开发与制造，以及口服制剂中关键辅料的供应。这些环节都存在各自的技术壁垒和竞争格局，直接影响着GLP-1类药物的成本、质量和市场供应。

5.3.1 原料药（API）的生产

GLP-1类药物多为多肽类生物药，其原料药的生产具有较高的技术壁垒：

  • 合成难度大： GLP-1类药物的分子结构复杂，包含几十个氨基酸残基，其多肽合成需要采用固相合成、液相合成或重组表达等多种先进技术。这些合成方法对工艺精密度、纯化技术和质量控制要求极高，以确保产品的一致性和安全性。例如，司美格鲁肽和替尔泊肽等长效GLP-1类似物，通常通过化学修饰（如脂肪酸侧链偶联、PEG化等）来延长半衰期，这进一步增加了合成的复杂性 。
  • 纯度与质量要求高： 作为注射或口服制剂的关键活性成分，GLP-1原料药的纯度要求极高，任何微量杂质都可能影响药物的疗效和安全性。生产过程需要严格遵守GMP（良好生产规范），对设备、人员和环境都有严格要求。
  • 产能壁垒： 随着全球GLP-1类药物需求的激增，原料药的产能已成为制约市场供应的关键因素。能够大规模、高效率、高品质生产GLP-1类多肽原料药的企业并不多，主要集中在少数掌握核心技术的专业多肽生产商或大型制药企业。例如，诺和诺德和礼来等原研药企通常拥有自己的原料药生产基地或长期合作的供应商，以确保供应的稳定性和独占性。国内市场也有部分企业布局GLP-1原料药的生产，但整体技术水平和产能规模仍有待提升，尤其是在长效和多靶点多肽的生产上。

5.3.2 注射给药装置

GLP-1类药物目前主要以注射剂形式给药，特别是预填充注射笔（pre-filled pen），其给药装置的设计和制造是上游产业链的另一个重要组成部分。

  • 技术复杂性与专利保护： 注射笔装置需要精密的设计和制造工艺，以确保患者使用的便捷性、准确性和安全性。这包括剂量调节机制、注射针头集成、安全性特征（如针头保护）以及易用性设计。许多注射装置技术都受到严格的专利保护，如诺和诺德的FlexTouch笔和礼来的KwikPen等，这些专利构成了重要的技术壁垒 99102。仿制药或生物类似药的开发商在设计自己的给药装置时，必须规避这些专利，或者寻求授权。
  • 用户体验与依从性： 良好的给药装置能够显著提升患者的使用体验和依从性。例如，长效GLP-1类药物通过一周一次的注射频率，配合易于操作的注射笔，降低了患者的治疗负担。口服GLP-1的研发，一定程度上也是为了解决注射剂给药的依从性问题。
  • 产能与供应链： 注射装置的生产需要专业的医疗器械制造商，其生产工艺和质量标准也需符合医疗器械相关法规。全球范围内能够大规模生产高质量预填充注射笔的企业相对有限，这使得给药装置的供应也可能成为GLP-1类药物市场供应的瓶颈之一。

5.3.3 口服制剂辅料

口服GLP-1类药物的成功上市（如口服司美格鲁肽Rybelsus）开启了新的给药途径，其关键在于特殊辅料的创新应用。

  • 吸收增强剂（如SNAC）： 口服司美格鲁肽的核心技术是利用吸收增强剂水杨酸钠（SNAC）来提高多肽在胃肠道的吸收。SNAC通过改变局部pH值和保护多肽免受酶降解，并促进其跨膜吸收，从而克服了口服多肽生物利用度低的难题 103。这种特殊的辅料具有很高的技术壁垒和专利保护，是口服GLP-1药物成功的关键。
    • 值得注意的是，SNAC的安全性问题也引发了关注。一项研究指出，SNAC可能通过与肉碱形成复合物，导致肉碱缺乏，特别是在易感个体中需要监测 103。
  • 新型口服递送系统： 除了SNAC，其他新型口服递送技术也在积极研发中，旨在进一步提高多肽的生物利用度和稳定性。这包括纳米颗粒、微胶囊、自乳化药物递送系统（SEDDS）等 104105106。例如，自乳化递送系统通过疏水离子对或干反胶束策略，能显著提高艾塞那肽等GLP-1受体激动剂的口服生物利用度 104。此外，口服基因疗法也是一个新兴方向，通过特定载体（如牛磺胆酸偶联硫酸鱼精蛋白和磷酸钙）递送GLP-1基因，实现内源性GLP-1的表达，在临床前研究中显示出超越注射剂的治疗效果 107。
  • 辅料供应商的专业性： 生产这些特殊辅料需要高度专业的化学合成能力和药用级生产标准。全球范围内能够提供符合要求的高质量吸收增强剂和新型递送系统辅料的供应商相对稀少，这构成了口服GLP-1类药物上游产业链的另一技术壁垒。

总结

GLP-1类药物的上游产业链竞争主要体现在技术壁垒和产能限制。在原料药生产方面，复杂的多肽合成技术和高标准的质量控制构成了核心壁垒。在注射给药装置方面，精密的设计、制造能力和专利保护是关键。而在口服制剂领域，新型吸收增强剂和递送系统辅料的创新和供应是决定其市场成败的重要因素。这些上游环节的竞争格局，将在很大程度上影响GLP-1类药物的整体市场供应、成本结构和最终的市场可及性。

6. 未来三年GLP-1类药物研发趋势与行业展望

6.1 技术研发趋势

未来三年，GLP-1类药物的研发将继续聚焦于提升疗效、拓展适应症、优化给药方式以及改善患者依从性。核心技术趋势将围绕多靶点激动剂、更长周期长效剂型以及非代谢类新适应症的拓展展开。

6.1.1 多靶点激动剂的持续创新

多靶点激动剂（Multi-target Agonists）代表了GLP-1类药物研发的下一代方向，旨在通过同时激活多个肠促胰素受体或其他代谢相关受体，实现更强的协同效应和更全面的代谢改善 108109。

  • GIP/GLP-1双靶点激动剂的优化与普及： 以替尔泊肽（Tirzepatide）为代表的GIP/GLP-1双靶点激动剂已证明其在降糖和减重方面的卓越疗效，未来三年将有更多类似的双靶点激动剂进入临床后期甚至上市阶段。研究将侧重于进一步优化分子的选择性、效价和药代动力学特性，以减少副作用并提升疗效。同时，针对不同人群（如亚洲人群）的疗效和安全性研究将进一步深化。
  • GLP-1/GIP/胰高糖素（Glucagon）三靶点激动剂的突破： 以Retatrutide为代表的GLP-1/GIP/胰高糖素三靶点激动剂已在II期临床中展现出前所未有的减重效果，高达24.2%的体重减轻使其有望比肩减重手术 75109。未来三年，此类三靶点激动剂的III期临床试验结果将陆续公布，并有望获得批准。研发重点将包括：
    • 平衡靶点激活： 如何精确平衡对GLP-1、GIP和胰高糖素受体的激活强度，以最大化减重和代谢益处，同时最小化潜在不良反应，是其技术关键。胰高糖素受体激活的潜在副作用需要精心管理 108。
    • 适应症拓展： 除了肥胖和2型糖尿病，这类药物在治疗非酒精性脂肪肝病（NAFLD）/代谢功能障碍相关脂肪性肝病（MASLD）方面的潜力将得到更深入的探索，因为胰高糖素具有促进脂肪分解和改善肝脏脂肪变性的作用。
  • GLP-1与其他激素联合激动剂的兴起： 除了上述三靶点，研究人员还在探索GLP-1与其他内源性激素（如胰淀素Amylin、纤维母细胞生长因子21 FGF21）的联合激动剂。
    • GLP-1/Amylin： 诺和诺德的Cagrisema（司美格鲁肽与长效胰淀素类似物Cagrilintide的固定复方制剂）已进入III期临床，其疗效预计将优于单一司美格鲁肽 75。这类药物有望进一步提升减重效果并改善饱腹感。
    • GLP-1/FGF21： FGF21类似物与GLP-1受体激动剂的联合，有望在改善血脂紊乱、肝脏脂肪变性以及胰岛素抵抗方面发挥协同作用。未来三年，将有更多此类创新疗法进入临床验证阶段。
  • 非肽类多靶点激动剂： 长期来看，开发具有多靶点作用的小分子非肽类激动剂将是重要方向，它们有望克服肽类药物的生物利用度限制，实现口服给药。天然产物作为多靶点治疗剂的潜力，为小分子非肽类激动剂的研发提供了新的思路 110。

6.1.2 更长周期长效剂型的开发

为进一步提升患者依从性，延长给药周期是GLP-1类药物研发的另一个重要方向。

  • 双周/月度注射剂： 目前主流的GLP-1类药物多为每周一次注射。未来三年，预计将有双周一次甚至每月一次的超长效GLP-1类激动剂进入临床或上市。这需要药物分子设计上的创新（如更长的半衰期）以及更先进的缓释技术。
  • 口服长效剂型的突破： 尽管口服司美格鲁肽已上市，但其生物利用度相对较低且有严格的服用限制。未来三年，口服递送技术的进步将专注于提高多肽的生物利用度，降低对服药条件的限制，例如利用新型吸收增强剂、纳米载体技术或非肽类小分子GLP-1激动剂。天然产物在克服生物利用度和代谢稳定性方面的挑战，为其在口服递送技术上的应用提供了借鉴 110。辉瑞等公司正在开发口服小分子GLP-1激动剂，这些药物有望实现更便捷的口服给药，并可能带来与注射剂相媲美的疗效。

6.1.3 非代谢类新适应症的拓展

GLP-1受体广泛分布于胰腺以外的多个组织，包括大脑、心脏、肾脏等 111112。因此，GLP-1类药物的潜在应用远超糖尿病和肥胖症，未来三年将在非代谢类适应症方面取得显著进展。

  • 心血管疾病： 尽管已有多项研究证实GLP-1类药物的心血管保护作用，未来的研究将更深入地探索其在心力衰竭伴或不伴2型糖尿病、慢性肾病患者心血管事件预防等方面的具体机制和疗效。
  • 神经退行性疾病： 越来越多的证据表明，GLP-1类药物可能具有神经保护作用，能够改善阿尔茨海默病（AD）和帕金森病等神经退行性疾病的病理生理过程。GLP-1受体激动剂可以减少神经炎症，促进神经生长，改善认知功能 111。研究表明，GLP-1受体激动剂是治疗阿尔茨海默病和2型糖尿病之间联系的潜在途径之一 113。
  • 非酒精性脂肪肝病（NAFLD）/代谢功能障碍相关脂肪性肝病（MASLD）： GLP-1类药物已被证实能改善肝脏脂肪变性。多靶点激动剂（特别是含胰高糖素受体激动成分的药物）在NAFLD/MASLD治疗中的应用将进一步拓展，有望成为该领域的突破性疗法。
  • 其他潜在适应症： 包括阻塞性睡眠呼吸暂停（OSA）、多囊卵巢综合征（PCOS）、慢性肾病，甚至成瘾性疾病（如戒烟、戒毒）等领域，GLP-1类药物的探索性研究正在进行中。例如，杜拉鲁肽正在研究用于戒烟，通过减轻尼古丁戒断症状和减少戒烟后体重增加来提高戒烟成功率。

总而言之，未来三年GLP-1类药物的研发将呈现多元化和精细化的趋势，多靶点、超长效和非代谢类适应症的拓展将是核心亮点。这些创新有望进一步提升药物的疗效和安全性，极大拓宽GLP-1类药物的临床应用前景，并最终改善全球数亿患者的健康状况。

6.2 市场发展预判

未来三年，GLP-1类药物市场将继续保持高速增长态势，这主要得益于其卓越的临床疗效、不断拓宽的适应症以及日益提升的患者认知度。全球及国内市场规模将显著扩大，患者渗透率持续增加，同时价格下行和医保覆盖将成为市场扩容的关键驱动力。

6.2.1 全球及国内市场规模增速

  • 全球市场规模： GLP-1类药物市场近年来一直保持强劲增长，并预计在未来几年继续高速扩张。根据市场分析报告，全球GLP-1受体激动剂市场预计将从2023年的约200-300亿美元增长到2030年超过1000亿美元，年复合增长率（CAGR）高达20%以上。尤其在肥胖症适应症获批后，市场潜力被进一步激发，预计到2026-2027年，全球市场规模将突破500亿美元。驱动因素包括新产品（如替尔泊肽）的上市和放量、适应症的持续扩展（如心血管结局、慢性肾病、非酒精性脂肪性肝炎等）以及不断增长的糖尿病和肥胖症患者群体。
  • 国内市场规模： 中国是全球糖尿病患者最多的国家，肥胖人口也持续增加，为GLP-1类药物提供了巨大的市场空间。虽然起步相对较晚，但随着利拉鲁肽、司美格鲁肽等产品陆续进入医保，以及国产创新药的加速上市，国内GLP-1市场增速将快于全球平均水平。预计未来三年内，中国GLP-1市场规模将从目前的数十亿元人民币迅速增长至数百亿元人民币，成为全球GLP-1市场的重要组成部分。特别是随着替尔泊肽等更高效药物的引入和医保谈判的推进，市场扩容速度将进一步加快。

6.2.2 患者渗透率变化

  • 2型糖尿病患者渗透率： 尽管GLP-1类药物在2型糖尿病治疗指南中地位日益提高，但目前的渗透率仍有巨大提升空间。在全球范围内，GLP-1类药物在2型糖尿病患者中的使用率仍相对较低，尤其是在早期治疗阶段。未来三年，随着医生对GLP-1类药物心血管和肾脏保护益处的认识加深，以及指南推荐力度的加强，其在2型糖尿病患者中的渗透率将持续提升，尤其是在伴有心血管疾病或高风险、慢性肾病的患者群体中，将成为优先选择。
  • 肥胖症患者渗透率： 肥胖症适应症的获批是GLP-1类药物市场渗透率爆发式增长的关键。司美格鲁肽（Wegovy）和替尔泊肽（Zepbound）在肥胖症治疗中展现出的卓越减重效果，正在改变临床医生和患者对肥胖症治疗的观念。目前，全球肥胖人口庞大，但接受有效药物治疗的比例极低。未来三年，随着肥胖症被更广泛地视为需要药物干预的慢性疾病，GLP-1类药物在超重和肥胖人群中的渗透率将大幅增加。然而，由于这些药物价格较高且部分国家医保覆盖有限，肥胖症患者的渗透率提升将面临支付能力的挑战。
  • 新适应症带来的渗透率： 随着GLP-1类药物在心力衰竭、慢性肾病、NASH、阻塞性睡眠呼吸暂停等非糖尿病非肥胖适应症领域的临床研究进展和获批，将进一步扩大其患者基础，带来新的市场增量和渗透率提升。

6.2.3 价格下行、医保覆盖对市场扩容的影响

价格和医保覆盖是影响GLP-1类药物市场可及性和扩容速度的决定性因素。

  • 价格下行趋势：
    1. 竞争加剧： 随着诺和诺德和礼来两大巨头之间的激烈竞争（如替尔泊肽与司美格鲁肽的头对头竞争），以及更多生物类似药和国产创新药的上市，市场竞争将促使药物价格出现下行压力。特别是原研药专利到期后，生物类似药的进入将进一步加速价格竞争。
    2. 国家采购政策： 在中国，国家药品集中采购（集采）和医保谈判是推动药品价格下降的主要手段。对于已上市的GLP-1类药物，通过医保谈判进入国家医保目录，通常需要以大幅降价为前提。虽然降价，但由于医保覆盖带来的放量效应，总销售额仍可能实现增长。
  • 医保覆盖的扩大：
    1. 可及性大幅提升： 医保覆盖是GLP-1类药物能够广泛惠及患者的关键。在全球大部分国家，包括中国，将GLP-1类药物纳入国家或商业医疗保险报销范围，将极大地降低患者的个人支付负担，从而显著提高药物的可及性和患者渗透率。
    2. 适应症覆盖： 目前，GLP-1类药物的医保覆盖主要集中在2型糖尿病适应症。未来三年，肥胖症适应症的医保覆盖将是市场扩容的重点。尽管一些国家（如日本）对肥胖症适应症的报销有严格限制 114，但随着GLP-1类药物在改善肥胖相关并发症（如心血管事件）方面的证据日益充分，预计将有更多国家逐步扩大其在肥胖症领域的医保覆盖范围，或至少对伴有严重合并症的肥胖患者提供报销。
    3. 对市场扩容的影响： 价格下行和医保覆盖将形成良性循环：医保谈判带来价格下降，降低患者用药门槛，扩大医保覆盖范围，进一步增加患者用药量，从而推动整体市场规模的爆发式增长。这对于长期依赖药物治疗的慢性疾病患者而言，是巨大的福音，也为药企提供了可持续的增长动力。

综上所述，未来三年GLP-1类药物市场将迎来黄金发展期。市场规模和患者渗透率将持续高速增长，其中价格下行和医保覆盖的扩大将是推动市场扩容的核心驱动力。这将促使GLP-1类药物从“高端奢侈品”逐步走向“大众必需品”，惠及更广泛的患者群体。

6.3 行业发展挑战

GLP-1类药物的快速发展和市场扩张伴随着一系列亟待解决的行业挑战，这些挑战在未来三年将愈发突出，主要体现在产能供给、不良反应监管和可及性提升等方面。

6.3.1 产能供给瓶颈

GLP-1类药物的市场需求呈现爆发式增长，尤其是司美格鲁肽和替尔泊肽在肥胖症适应症获批后，全球范围内出现了持续的供应短缺问题。

  • 生产工艺复杂性： GLP-1类药物大多是多肽类生物药，其原料药（API）的合成过程复杂，需要精密的化学合成或重组技术，纯化要求高，生产周期长。例如，诺和诺德和礼来等巨头为了应对需求，虽已投入巨资扩建产能，但短期内难以完全满足市场需求 。
  • 上游供应链限制： 除了核心原料药，注射给药装置（如预填充注射笔）的精密制造也存在技术壁垒和产能限制。口服剂型所需的特殊辅料（如口服司美格鲁肽中的SNAC）也面临生产技术和供应能力的要求。这些上游环节的瓶颈相互叠加，共同限制了终端产品的供应。
  • 短期内难以缓解： 产能扩建是一个漫长且资本密集的过程，涉及车间建设、设备采购、人员培训和严格的质量验证。因此，预计在未来三年内，尤其对于高剂量的减重适应症产品，产能短缺仍将是制约市场进一步放量的核心问题。
  • 应对方向： 药企需持续加大生产投资，优化生产工艺，并与多个具备资质的第三方生产商建立合作，分散风险。同时，需加强对上游供应链的垂直整合和风险管理，确保关键原材料和零部件的稳定供应。

6.3.2 不良反应监管与长期安全性再评估

尽管GLP-1类药物整体安全性良好，但随着使用人群扩大和长期用药，对不良反应的持续监测和深入研究至关重要。

  • 胃肠道不良反应管理： 恶心、呕吐、腹泻等胃肠道不适是GLP-1类药物最常见的副作用，部分患者因此停药。未来需要更精细化的剂量滴定方案、更好的患者教育和支持，以及可能的新型抗恶心药物来管理这些副作用，以提高患者依从性 。
  • 罕见或长期风险的再评估：
    • 胆道疾病： 司美格鲁肽已显示出增加胆道疾病（如胆石症）风险的可能性，这可能与快速减重有关。未来需要更深入的研究来明确其发病机制，并制定高风险人群的筛查和管理策略 。
    • 肿瘤风险： 虽然目前无确凿证据表明GLP-1类药物增加胰腺癌或甲状腺髓样癌风险，但这类长期、罕见事件的评估需要更长时间的大规模真实世界数据。对肾癌和结直肠癌等其他肿瘤风险的初步信号，也需要严格的流行病学研究来证实或排除 。
    • 精神健康问题： 有研究指出，GLP-1受体激动剂可能与抑郁症和自杀意念的发生有关，尽管目前尚未建立明确的因果关系。未来三年，监管机构和药企需要加强对这类精神健康不良事件的监测和分析，并及时更新用药指南 。
    • 其他潜在风险： 随着GLP-1类药物在非代谢类适应症（如多发性硬化症）中的探索，需要关注药物在这些新适应症中的独特安全性风险 115。
  • 停药反弹的长期管理： 停药后体重和血糖反弹是普遍现象，提示肥胖和2型糖尿病的慢性病管理属性。监管部门和医学界需明确GLP-1类药物的长期用药原则，并鼓励探索缓解停药反弹的综合干预策略，包括生活方式干预、序贯治疗等 。
  • 应对方向： 监管机构应加强上市后药物警戒，收集和分析真实世界数据；药企应主动开展长期安全性研究，并优化患者教育材料，提供更详细的不良反应管理指导。

6.3.3 可及性提升的挑战

GLP-1类药物的高昂价格和有限的医保覆盖是阻碍其广泛可及性的主要障碍。

  • 支付能力与可负担性： 在许多国家，GLP-1类药物的月治疗成本高昂，超出许多患者的支付能力 116。即使有保险覆盖，自付部分也可能很高。这种经济负担限制了药物在低收入人群和发展中国家的普及。
  • 医保覆盖的滞后性： 尽管GLP-1类药物在2型糖尿病中的医保覆盖逐渐扩大，但在肥胖症等新兴适应症的医保覆盖仍面临挑战。许多医疗保险系统尚未将肥胖症完全视为需要长期药物治疗的慢性疾病，导致报销政策迟滞。
  • 非法渠道购买与假药风险： 由于市场需求旺盛、价格昂贵和处方限制，一些患者转向非法渠道购买“研究用途”的GLP-1类药物或假冒伪劣产品，这带来了严重的产品质量和患者安全风险 117118119120。假药可能含量不准确，甚至含有有毒物质，对患者健康造成威胁。
  • 医生认知与培训： 许多医生对GLP-1类药物的最新适应症、剂量滴定、不良反应管理和长期用药策略的认知仍不足，缺乏充分的培训，也限制了药物的合理使用。
  • 应对方向：
    • 价格策略与支付模式创新： 药企需要探索更灵活的价格策略，如基于疗效的支付模式、分层定价等，以适应不同市场的支付能力。同时，积极与保险公司合作，争取更广泛的医保覆盖。
    • 打击非法销售： 监管机构应加强对在线非法销售的打击力度，提高公众对假药风险的认识，并通过合法渠道保障药物的供应和可及性。
    • 提升医疗专业人员教育： 开展广泛的医学教育项目，提升医生对GLP-1类药物的认知和管理能力，确保药物的合理处方和使用。
    • 生物类似药与国产药： 随着原研药专利到期，生物类似药和国产创新药的上市将带来价格竞争，从而提升药物的可及性。

综上所述，未来三年GLP-1类药物行业在产能、安全监管和可及性方面将面临严峻挑战。能否有效应对这些挑战，将决定该类药物能否持续健康发展，真正惠及全球广大的糖尿病和肥胖症患者。

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参考文献

1Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.PubMed

Daniel J Drucker
Cell Metab. 2018 Apr 3;27(4):740-756. doi: 10.1016/j.cmet.2018.03.001.
Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.

2Biology of incretins: GLP-1 and GIP.PubMed

Laurie L Baggio, Daniel J Drucker
Gastroenterology. 2007 May;132(6):2131-57. doi: 10.1053/j.gastro.2007.03.054.
This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

3GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review.PubMed

Nasreen Alfaris, Stephanie Waldrop, Veronica Johnson, et al.
EClinicalMedicine. 2024 Aug 30;75:102782. doi: 10.1016/j.eclinm.2024.102782. eCollection 2024 Sep.
UNLABELLED: Obesity and type 2 diabetes mellitus (T2DM) present major global health challenges, with an increasing prevalence worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a pivotal treatment option for both conditions, demonstrating efficacy in blood glucose management, weight reduction, cardiovascular disease prevention, and kidney health improvement. GLP-1, an incretin hormone, plays a crucial role in glucose metabolism and appetite regulation, influencing insulin secretion, insulin sensitivity, and gastric emptying. The therapeutic use of GLP-1RAs has evolved significantly, offering various formulations that provide different efficacy, routes of administration, and flexibility in dosing. These agents reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects, making them an integral component of T2DM and obesity management. This review will discuss the currently approved medication for T2DM and obesity, and will also highlight the advent of novel agents which are dual and triple hormonal agonists which represent the future direction of incretin-based therapy. FUNDING: National Institutes of HealthNIDDKU24 DK132733 (FCS), UE5 DK137285 (FCS), and P30 DK040561 (FCS).

4GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art.PubMed

Michael A Nauck, Daniel R Quast, Jakob Wefers, et al.
Mol Metab. 2021 Apr;46:101102. doi: 10.1016/j.molmet.2020.101102. Epub 2020 Oct 14.
BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW: To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

5Semaglutide lowers body weight in rodents via distributed neural pathways.PubMed

Sanaz Gabery, Casper G Salinas, Sarah J Paulsen, et al.
JCI Insight. 2020 Mar 26;5(6):133429. doi: 10.1172/jci.insight.133429.
Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.

6Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism.PubMed

Diba Borgmann, Elisa Ciglieri, Nasim Biglari, et al.
Cell Metab. 2021 Jul 6;33(7):1466-1482.e7. doi: 10.1016/j.cmet.2021.05.002. Epub 2021 May 26.
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.

7Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists.PubMed

Jamy Ard, Angela Fitch, Sharon Fruh, et al.
Adv Ther. 2021 Jun;38(6):2821-2839. doi: 10.1007/s12325-021-01710-0. Epub 2021 May 11.
Obesity is a chronic disease associated with many complications. Weight loss of 5-15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Pharmacotherapy can help people with obesity achieve and maintain their target weight loss, thereby reducing the risk of obesity-related complications. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. Reasons for low levels of initiation and long-term use of AOMs may include reluctance of public health and medical organizations to recognize obesity as a disease, lack of reimbursement, provider inexperience, and misperceptions about the efficacy and safety of available treatments. This article aims to inform primary care providers about the mechanism of action of one class of AOMs, glucagon-like peptide 1 receptor agonists (GLP-1RAs), in weight loss and longer-term maintenance of weight loss, and the efficacy and safety of this treatment class. GLP-1RA therapy was initially developed to treat type 2 diabetes. Owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg has been approved, and once-weekly subcutaneous administration of semaglutide 2.4 mg is being investigated in phase III trials, for obesity management. Considerations regarding adverse effects and contraindications for different drug classes are provided to help guide treatment decision-making when considering pharmacotherapy for weight management in patients with obesity.

8Biomarkers of satiation and satiety.PubMed

Cees de Graaf, Wendy A M Blom, Paul A M Smeets, et al.
Am J Clin Nutr. 2004 Jun;79(6):946-61. doi: 10.1093/ajcn/79.6.946.
This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (<5 min), which have been shown to be involved in meal initiation; leptin changes during longer-term (>2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.

9The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss.PubMed

Anna Secher, Jacob Jelsing, Arian F Baquero, et al.
J Clin Invest. 2014 Oct;124(10):4473-88. doi: 10.1172/JCI75276. Epub 2014 Sep 9.
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.

10Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism.PubMed

Tong Bu, Ziyan Sun, Yi Pan, et al.
Diabetes Metab J. 2024 May;48(3):354-372. doi: 10.4093/dmj.2023.0277. Epub 2024 Apr 1.
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.

11GLP-1-based medications: Mechanisms involved in obesity treatment.PubMed

Javier Salvador
Med Clin (Barc). 2025 Jul;165(1):107035. doi: 10.1016/j.medcli.2025.107035. Epub 2025 Jun 3.
Thanks to biochemical engineering, the glucagon-like peptide-1 (GLP-1) molecule has emerged as an essential element in the development of diverse agonists and multiagonists, based in the GLP-1 structure for obesity treatment. These new antiobesity medications can reach up to 24% weight loss, which makes possible an effective management of obesity and its complications. GLP-1 agonists affect diverse obesity etiopathogenic processes such as abnormal food intake regulation, adipocyte dysfunction, insulin resistance, adipokine production, inflammation, endothelial dysfunction, lipid metabolism, and oxidative stress. All these factors are significantly involved in the pathophysiology of multiple obesity-related complications, including diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, heart failure, and atherosclerosis, among others. Potentiation and complementation of GLP-1 effects by co-stimulation of GIP (glucose-dependent insulinotropic peptide), glucagon, or amylin and other receptors contribute to additional benefits, opening new horizons in the therapeutic individualization for persons living with obesity.

12Incretins and Lipid Metabolism.PubMed

Vasilis Tsimihodimos, Moses Elisaf
Curr Med Chem. 2018;25(18):2133-2139. doi: 10.2174/0929867324666170414164244.
BACKGROUND: Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. OBJECTIVE: To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. METHODS: PubMed was searched using the terms "incretins", "GLP-1", "GIP" and "lipids", "dyslipidemia", "triglycerides", "apolipoprotein B48". All articles published in the English language until June 2016 were assessed and the relevant information is presented here. RESULTS: GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. CONCLUSION: GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.

13Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction.PubMed

Michael A Nauck, David A D'Alessio
Cardiovasc Diabetol. 2022 Sep 1;21(1):169. doi: 10.1186/s12933-022-01604-7.
Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

14Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.PubMed

Qiyuan Keith Liu
Front Endocrinol (Lausanne). 2024 Jul 24;15:1431292. doi: 10.3389/fendo.2024.1431292. eCollection 2024.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

15Pharmacology, physiology, and mechanisms of incretin hormone action.PubMed

Jonathan E Campbell, Daniel J Drucker
Cell Metab. 2013 Jun 4;17(6):819-837. doi: 10.1016/j.cmet.2013.04.008. Epub 2013 May 16.
Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies.

16How May GIP Enhance the Therapeutic Efficacy of GLP-1?PubMed

Ricardo J Samms, Matthew P Coghlan, Kyle W Sloop
Trends Endocrinol Metab. 2020 Jun;31(6):410-421. doi: 10.1016/j.tem.2020.02.006. Epub 2020 Mar 16.
Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering.

17Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.PubMed

Ajit Regmi, Eitaro Aihara, Michael E Christe, et al.
Cell Metab. 2024 Jul 2;36(7):1534-1549.e7. doi: 10.1016/j.cmet.2024.05.010. Epub 2024 Jun 14.
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

18Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.PubMed

Francis S Willard, Jonathan D Douros, Maria Bn Gabe, et al.
JCI Insight. 2020 Sep 3;5(17):140532. doi: 10.1172/jci.insight.140532.
Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

19GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other?PubMed

S Brunton
Int J Clin Pract. 2014 May;68(5):557-67. doi: 10.1111/ijcp.12361. Epub 2014 Feb 6.
BACKGROUND: In patients with type 2 diabetes (T2D), incretin-based therapies improve glycaemic control with low incidence of hypoglycaemia and without weight gain, both advantages over traditional add-ons to metformin. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered orally and provide a physiological increase in glucagon-like peptide-1 (GLP-1) levels, while GLP-1 receptor agonists (GLP-1RAs) are injectable and deliver pharmacological levels of GLP-1RA. This review aims to distinguish between GLP-1RAs and DPP-4 inhibitors, and discuss when each may be favoured in clinical practice. METHODS: A MEDLINE search, limited to human clinical trials and using the search criteria 'GLP-1RA' or 'DPP-4 inhibitor', identified seven head-to-head studies and one relevant post hoc analysis (all a GLP-1RA vs. the DPP-4 inhibitor sitagliptin). In combination with treatment algorithms, product prescribing information and personal clinical experience, these studies were used to compare the efficacy and suitability of GLP-1RAs and DPP-4 inhibitors in patients with T2D. RESULTS: In head-to-head clinical trials, GLP-1RAs provided greater glycaemic control, weight loss and overall treatment satisfaction vs. the DPP-4 inhibitor sitagliptin. Transient nausea was more frequent with GLP-1RAs and should be addressed through patient education and an incremental dosing approach. Current treatment algorithms recommend incretin-based therapy use after metformin failure, but local guidance may restrict their use. CONCLUSION: GLP-1RAs provide superior glycaemic control and weight loss vs. DPP-4 inhibitors in patients with T2D. DPP-4 inhibitors may sometimes be preferred to a GLP-1RA if weight is not a concern, oral administration is a desirable feature or when a GLP-1RA cannot be tolerated.

20Newer anti-diabetic therapies with low hypoglycemic risk-potential advantages for frail older people.PubMed

Demelza Emmerton, Ahmed Abdelhafiz
Hosp Pract (1995). 2021 Aug;49(3):164-175. doi: 10.1080/21548331.2021.1905414. Epub 2021 Apr 5.
The prevalence of diabetes is increasing due to increasing aging of the population. Hypoglycemia is a common diabetes-related complication in old age especially in patients with multiple comorbidities and frailty. Hypoglycemia and frailty appear to have a bidirectional relationship reenforcing each other in a negative downhill spiral that leads to an increased risk of adverse events including disability and mortality. The incidence of hypoglycemia in this age group is usually underestimated due to its atypical clinical presentation and difficult recognition by health care professionals. Guidelines generally recommend a relaxed glycemic control in frail older people with diabetes mainly due to the fear of anti-diabetic medications-induced hypoglycemia. The new anti-diabetic therapies of sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RA) have consistently shown a cardio-renal protective effect independent of their glycemic control. Contrary to the traditional hypoglycemic agents that either increase insulin stimulation or insulin sensitization with a potential hypoglycemic risk especially sulfonylureas, the new therapies have a novel anti-diabetic mechanisms of action that have a negligible risk of hypoglycemia. The new therapies appear to be both effective and well tolerated in old age. With appropriate patients' selection, most older people will be eligible for the new therapies if well tolerated and no contraindications. In frail older people, we suggest a pragmatic approach of the use of the new therapies based on the concept of the weight status rather than the frailty status. Frail patients with normal or excess weight are likely to gain most from the new therapies due to its favorable metabolic properties in this group, while the use in the underweight frail patients should be largely avoided especially in those with persistent anorexia and weight loss.

21Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes.PubMed

André J Scheen, Luc F Van Gaal
Lancet Diabetes Endocrinol. 2014 Nov;2(11):911-22. doi: 10.1016/S2213-8587(14)70004-X. Epub 2014 Feb 19.
The increasing prevalence of obesity is contributing substantially to the ongoing epidemic of type 2 diabetes. Abdominal adiposity, a feature of ectopic fat syndrome, is associated with silent inflammation, abnormal hormone secretion, and various metabolic disturbances that contribute to insulin resistance and insulin secretory defects, resulting in type 2 diabetes, and induce a toxic pattern that leads to cardiovascular disease, liver pathologies, and cancer. Despite the importance of weight control strategies in the prevention and management of type 2 diabetes, long-term results from lifestyle or drug interventions are generally disappointing. Furthermore, most of the classic glucose-lowering drugs have a side-effect of weight gain, which renders the management of most overweight or obese people with type 2 diabetes even more challenging. Many anti-obesity pharmacological drugs targeting central control of appetite were withdrawn from the market because of safety concerns. The gastrointestinal lipase inhibitor orlistat was the only anti-obesity drug available until the recent US, but not European, launch of phentermine-controlled-release topiramate and lorcaserin. Improved knowledge about bodyweight regulation opens new prospects for the potential use of peptides derived from the gut or the adipose tissue. Combination therapy will probably be necessary to avoid compensatory mechanisms and potentiate initial weight loss while avoiding weight regain. New glucose-lowering treatments, especially glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, offer advantages over traditional antidiabetic drugs by promoting weight loss while improving glucose control. In this Review, we explore the overlapping pathophysiology and also how various treatments can, alone or in combination, combat the dual burden of obesity and type 2 diabetes.

22Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus.PubMed

Kjeld Hermansen, Lene S Mortensen
Drug Saf. 2007;30(12):1127-42. doi: 10.2165/00002018-200730120-00005.
The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes. Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides such as metformin have been consistently shown to have a beneficial effect on weight; metformin appears to modestly reduce weight when used as a monotherapy. alpha-Glucosidase inhibitors are considered weight neutral; in fact, the results of some studies show that they cause reductions in weight. Thiazolidinediones (TZDs) are typically associated with weight gain and increased risk of oedema, while the impact of some TZDs, such as pioglitazone, on lipid homeostasis could be beneficial. Insulin, the most effective therapy when oral agents are ineffective, has always been linked to significant weight gain. Newly developed insulin analogues can lower the risk of hypoglycaemia compared with human insulin, but most have no advantage in terms of weight gain. The basal analogue insulin detemir, however, has been demonstrated to cause weight gain to a lesser extent than human insulin. The emerging treatments, such as glucagon-like peptide-1 agonists and the amylin analogue, pramlintide, seem able to decrease weight in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 inhibitors seem to be weight neutral. In summary, while reduction of hyperglycaemia remains the foremost goal in the treatment of patients with type 2 diabetes, the avoidance of weight gain may be a clinically important secondary goal. This is already possible with careful selection of available therapies, while several emerging therapies promise to further extend the options available.

23[Effects of anti-diabetic therapy on overweight/obesity and dyslipidemia: traditional hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones) versus glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors].PubMed

Teresa Vanessa Fiorentino, Giorgio Sesti
G Ital Cardiol (Rome). 2013 Dec;14(12 Suppl):15-25. doi: 10.1714/1375.15277.
Obesity and dyslipidemia often coexist in patients with type 2 diabetes and contribute to increase the risk of cardiovascular events. Pharmacological treatments of diabetes often result in weight gain, an undesirable event associated with a worse cardiovascular risk profile and decreased adherence to therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have been shown to improve glycemic control without promoting weight gain and to exert beneficial effects on lipid profile by reducing total and LDL cholesterol, triglycerides, and free fatty acid levels. DPP-4 inhibitors have demonstrated to be weight neutral whereas treatment with GLP-1 analogs is associated with a significant weight loss. DPP-4 and GLP-1 analogs represent a new therapeutic option for type 2 diabetes, which offers the advantage of combining glycemic control with beneficial effects on body weight and lipid profile, thus providing greater cardiovascular protection.

24Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets.PubMed

Francesco Piccirillo, Sara Mastroberardino, Annunziata Nusca, et al.
Int J Mol Sci. 2023 Jun 15;24(12):10164. doi: 10.3390/ijms241210164.
Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.

25Cardiovascular efficacy and safety of antidiabetic agents: A network meta-analysis of randomized controlled trials.PubMed

Minji Sohn, Juan P Frias, Soo Lim
Diabetes Obes Metab. 2023 Dec;25(12):3560-3577. doi: 10.1111/dom.15251. Epub 2023 Aug 30.
AIM: An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs. MATERIALS AND METHODS: Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates. RESULTS: Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo. CONCLUSIONS: GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.

26Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO).PubMed

Ian H de Boer, Kamlesh Khunti, Tami Sadusky, et al.
Diabetes Care. 2022 Dec 1;45(12):3075-3090. doi: 10.2337/dci22-0027.
People with diabetes and chronic kidney disease (CKD) are at high risk for kidney failure, atherosclerotic cardiovascular disease, heart failure, and premature mortality. Recent clinical trials support new approaches to treat diabetes and CKD. The 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease each provide evidence-based recommendations for management. A joint group of ADA and KDIGO representatives reviewed and developed a series of consensus statements to guide clinical care from the ADA and KDIGO guidelines. The published guidelines are aligned in the areas of CKD screening and diagnosis, glycemia monitoring, lifestyle therapies, treatment goals, and pharmacologic management. Recommendations include comprehensive care in which pharmacotherapy that is proven to improve kidney and cardiovascular outcomes is layered on a foundation of healthy lifestyle. Consensus statements provide specific guidance on use of renin-angiotensin system inhibitors, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist. These areas of consensus provide clear direction for implementation of care to improve clinical outcomes of people with diabetes and CKD.

27Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.PubMed

Suetonia C Palmer, Britta Tendal, Reem A Mustafa, et al.
BMJ. 2021 Jan 13;372:m4573. doi: 10.1136/bmj.m4573.
OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.

28Obesity Management in Adults: A Review.PubMed

Arielle Elmaleh-Sachs, Jessica L Schwartz, Carolyn T Bramante, et al.
JAMA. 2023 Nov 28;330(20):2000-2015. doi: 10.1001/jama.2023.19897.
IMPORTANCE: Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death. OBSERVATIONS: A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide has the greatest effect, with mean weight loss of 21% at 72 weeks. Endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) can attain 10% to 13% weight loss at 6 months. Weight loss from metabolic and bariatric surgeries (ie, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) ranges from 25% to 30% at 12 months. Maintaining long-term weight loss is difficult, and clinical guidelines support the use of long-term antiobesity medications when weight maintenance is inadequate with lifestyle interventions alone. CONCLUSION AND RELEVANCE: Obesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.

29Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies.PubMed

Ian J Neeland, Jennifer Linge, Andreas L Birkenfeld
Diabetes Obes Metab. 2024 Sep;26 Suppl 4:16-27. doi: 10.1111/dom.15728. Epub 2024 Jun 27.
Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.

30Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study.PubMed

Yu-Nan Huang, Wen-Ling Liao, Jing-Yang Huang, et al.
Diabetes Obes Metab. 2024 Nov;26(11):5222-5232. doi: 10.1111/dom.15869. Epub 2024 Aug 22.
AIM: We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). MATERIALS AND METHODS: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. RESULTS: After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. CONCLUSIONS: In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

31Socioeconomic and Demographic Inequalities in Off-Label Prescription of Glucagon-Like Peptide-1 Receptor Agonists: A Swedish Descriptive Cohort Study.PubMed

Laura Pazzagli, Ylva Trolle Lagerros
Obes Facts. 2025;18(2):130-138. doi: 10.1159/000542682. Epub 2024 Nov 26.
INTRODUCTION: In Sweden, glucagon-like peptide-1 (GLP-1) receptor agonists are subsidized for diabetes indication but not for obesity. Unregulated off-label prescription of GLP-1 receptor agonists for obesity treatment may raise concerns about potential inequalities for both patient groups. This study aimed to describe socioeconomic and demographic characteristics of on- and off-label users of GLP-1 receptor agonists in persons without a diagnosis of diabetes. METHODS: This is a Swedish descriptive register-based cohort study of persons who filled a prescription of a GLP-1 receptor agonist at least once during 2018-2022. Individuals were excluded from the study population if they had a diagnosis of diabetes or previous prescription fills of insulin/analogs at any time prior to the first filled prescription of a GLP-1 receptor agonist. Socioeconomic and demographic characteristics were described overall and stratified by sex and prior use of anti-obesity medications. Off-label use was defined by filled prescriptions of GLP-1 receptor agonists which are indicated for diabetes treatment. RESULTS: The study population included 16,436 individuals, of which 70.1% were women, 30.7% had previously filled a prescription of anti-obesity medications, and 65.3% had Sweden as country of origin and 17.2% an Asian country. In the analyses stratified by sex, women were more likely to have an education longer than 9 years (84.8% vs. 78.3% in men). Nonetheless, women had lower annual individual (2,891.3 vs. 4,004.9 in men) and family disposable income (5,645.5 vs. 6,092.5 in men). Overall, on-label prescription was higher in women (49.2% vs. 30.9% in men), while off-label was more common among men (69% vs. 51% in women). Trends of GLP-1 users per 1,000 inhabitants showed four-fold variation between counties. CONCLUSION: High family disposable income and male sex are common among off-label GLP-1 receptor agonist users compared to users of the only on-label GLP-1 receptor agonist available in Sweden during the study period. Large variation between counties indicates different clinical practices and guideline interpretations.

32Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation.PubMed

Juris J Meier
Front Endocrinol (Lausanne). 2021 Jun 25;12:645617. doi: 10.3389/fendo.2021.645617. eCollection 2021.
Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs.

33Clinical review of subcutaneous semaglutide for obesity.PubMed

Anna Phillips, Jennifer N Clements
J Clin Pharm Ther. 2022 Feb;47(2):184-193. doi: 10.1111/jcpt.13574. Epub 2021 Dec 28.
WHAT IS KNOWN AND OBJECTIVE: The purpose of this review paper is to review the efficacy and safety of subcutaneous semaglutide, marketed as Wegovy, a glucagon-like peptide-1 receptor agonist for obesity management. METHODS: A MEDLINE search (1970 to June 2021) was conducted to identify Phase 3 trials of subcutaneous semaglutide for obesity management. Published Phase 3 trials from The Semaglutide Treatment Effect in People with obesity (STEP) program were reviewed and summarized. RESULTS AND DISCUSSION: Based on four Phase 3 trials, subcutaneous semaglutide as 2.4 mg once weekly was compared in efficacy and safety among 5000 randomized participants who were overweight or had obesity. A change in body weight from baseline to end of study was the primary outcome in the STEP program. Participants who received semaglutide had a dose-dependent reduction in body weight from baseline, compared to placebo. Higher percentages of participants had 5%-10% weight reduction from baseline when receiving subcutaneous semaglutide. The patient population was mainly middle-aged female participants with Class II obesity. Additional studies are needed, especially active-comparator trials, to determine the efficacy and safety of semaglutide in a diverse patient population. WHAT IS NEW AND CONCLUSION: Subcutaneous semaglutide is another available option as adjunct therapy to lifestyle modifications for people who are overweight or have obesity based on body weight and body mass index. It resulted in more weight reduction than placebo with gastrointestinal adverse events being the most common safety concerns. Clinical utilization of subcutaneous semaglutide will be determined, as insurance coverage will be a limitation for this new medication.

34Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.PubMed

Hanna Clementine Tan, Oliver Allan Dampil, Maricar Mae Marquez
J ASEAN Fed Endocr Soc. 2022;37(2):65-72. doi: 10.15605/jafes.037.02.14. Epub 2022 Aug 23.
BACKGROUND: The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes. METHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model. RESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), <0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], <0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], =0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], =0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis. CONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. However, risk of gastrointestinal adverse events, discontinuation of treatment and serious adverse events were higher in the semaglutide group versus placebo.

35Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.PubMed

Areesha Moiz, Jeremy Y Levett, Kristian B Filion, et al.
Am J Cardiol. 2024 Jul 1;222:121-130. doi: 10.1016/j.amjcard.2024.04.041. Epub 2024 Apr 26.
Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.

36Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials.PubMed

Mihaela-Simona Popoviciu, Lorena Păduraru, Galal Yahya, et al.
Int J Mol Sci. 2023 Jun 21;24(13):10449. doi: 10.3390/ijms241310449.
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.

37Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide.PubMed

Baptist Gallwitz, Francesco Giorgino
Front Endocrinol (Lausanne). 2021 Jun 29;12:645507. doi: 10.3389/fendo.2021.645507. eCollection 2021.
Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

38Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics.PubMed

Stephen J Nicholls, Deepak L Bhatt, John B Buse, et al.
Am Heart J. 2024 Jan;267:1-11. doi: 10.1016/j.ahj.2023.09.007. Epub 2023 Sep 25.
BACKGROUND: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial. METHODS: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis). RESULTS: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing. CONCLUSION: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.

39Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.PubMed

Stephen J Nicholls, Imre Pavo, Deepak L Bhatt, et al.
N Engl J Med. 2025 Dec 18;393(24):2409-2420. doi: 10.1056/NEJMoa2505928.
BACKGROUND: Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. METHODS: We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. RESULTS: A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).

40Tirzepatide Once Weekly for the Treatment of Obesity.PubMed

Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad, et al.
N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4.
BACKGROUND: Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known. METHODS: In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population. RESULTS: At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively. CONCLUSIONS: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).

41Tirzepatide for Weight Reduction in Chinese Adults With Obesity: The SURMOUNT-CN Randomized Clinical Trial.PubMed

Lin Zhao, Zhifeng Cheng, Yibing Lu, et al.
JAMA. 2024 Aug 20;332(7):551-560. doi: 10.1001/jama.2024.9217.
IMPORTANCE: Obesity has become a global public health concern and China has the largest number of affected people worldwide. OBJECTIVE: To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes. INTERVENTIONS: Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks. MAIN OUTCOMES AND MEASURES: Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population. RESULTS: Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%). CONCLUSIONS AND RELEVANCE: In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05024032.

42Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.PubMed

Louis J Aronne, Naveed Sattar, Deborah B Horn, et al.
JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945.
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.

43Tirzepatide for metabolic dysfunction-associated steatohepatitis: results from phase II clinical trials and perspectives.PubMed

Stefano Fiorucci, Ginevra Urbani
Expert Opin Investig Drugs. 2025 Sep;34(9):655-663. doi: 10.1080/13543784.2025.2546812. Epub 2025 Aug 25.
INTRODUCTION: Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities. AREAS COVERED: Results from SYNERGY-NASH, a phase 2 study involving patients with biopsy-proven MASH and stage 2 or 3 fibrosis, have shown that tirzepatide achieved MASH resolution with no worsening of fibrosis in a significantly higher percentage of patients than placebo. Additionally, more patients in the tirzepatide group in comparison to placebo achieved a 1-stage or greater fibrosis improvement without worsening of MASH, but the study was not powered to detect this change, and noninvasive biomarkers of fibrosis were not significantly improved. EXPERT OPINION: While these results suggest a potential role for tirzepatide in MASH treatment given its ability to improve insulin sensitivity and reduce food intake, factors already shown to be beneficial in reducing livers steatosis and fibrosis, larger clinical trials are needed.

44Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.PubMed

Atul Malhotra, Ronald R Grunstein, Ingo Fietze, et al.
N Engl J Med. 2024 Oct 3;391(13):1193-1205. doi: 10.1056/NEJMoa2404881. Epub 2024 Jun 21.
BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

45Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.PubMed

Thomas Karagiannis, Konstantinos Malandris, Ioannis Avgerinos, et al.
Diabetologia. 2024 Jul;67(7):1206-1222. doi: 10.1007/s00125-024-06144-1. Epub 2024 Apr 13.
AIMS/HYPOTHESIS: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA and body weight from baseline. Secondary outcomes were achievement of HbA target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. CONCLUSIONS/INTERPRETATION: Our data show that s.c. tirzepatide had a more pronounced effect on HbA and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. REGISTRATION: PROSPERO registration no. CRD42022382594.

46Comparative effectiveness of glucagon-like peptide-1 receptor agonists for the management of obesity in adults without diabetes: A network meta-analysis of randomized clinical trials.PubMed

Omar S Alkhezi, Abdullah A Alahmed, Osamah M Alfayez, et al.
Obes Rev. 2023 Mar;24(3):e13543. doi: 10.1111/obr.13543. Epub 2022 Dec 29.
Tirzepatide is a new glucagon-like peptide-1 receptor agonist (GLP-1RA) that has shown promising results for weight loss. A Bayesian network meta-analysis was conducted to compare the efficacy and safety of GLP-1RAs for obesity management. Embase and MEDLINE were searched looking for randomized clinical trials (RCTs) that evaluated the efficacy of GLP-1RAs for weight loss in patients without diabetes. The main efficacy outcomes evaluated were the mean change in actual and percentage weight loss and the proportion of patients with weight loss of ≥5%-20%. Main safety outcomes evaluated include nausea, vomiting, diarrhea, constipation, loss of appetite, pancreatitis, gallbladder-related disorders, and withdrawal due to adverse events. Seven RCTs with more than 12,300 patients were analyzed, including patients with body mass index (BMI) ≥ 30 kg/m , or BMI ≥ 27 kg/m with comorbidities. Weekly tirzepatide 10 and 15 mg resulted in more weight loss than weekly semaglutide 2.4 mg, daily semaglutide 0.4 mg, or liraglutide 3 mg. Tirzepatide and weekly semaglutide demonstrated comparable results but with significantly higher odds of achieving ≥5%-20% weight loss compared with liraglutide. GLP-1RAs triggered more gastrointestinal adverse events than placebo, with no in-between difference. Although all GLP-1RAs lead to significant weight reduction, tirzepatide was associated with better efficacy outcomes while having a comparable safety profile.

47Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.PubMed

Zeyu Xie, Guimei Zheng, Zhuoru Liang, et al.
Metabolism. 2024 Dec;161:156038. doi: 10.1016/j.metabol.2024.156038. Epub 2024 Sep 19.
PURPOSE: This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. METHODS: Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. RESULTS: Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. CONCLUSION: Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

48Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.PubMed

Louis J Aronne, Deborah Bade Horn, Carel W le Roux, et al.
N Engl J Med. 2025 Jul 3;393(1):26-36. doi: 10.1056/NEJMoa2416394. Epub 2025 May 11.
BACKGROUND: Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. METHODS: In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. RESULTS: A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. CONCLUSIONS: Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).

49The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.PubMed

Sten Madsbad, Jens J Holst
Expert Opin Investig Drugs. 2025 Mar;34(3):197-215. doi: 10.1080/13543784.2025.2472408. Epub 2025 Mar 1.
INTRODUCTION: GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes. AREAS COVERED: This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration. EXPERT OPINION: The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

50Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials.PubMed

Rune V Overgaard, Andrea Navarria, Steen H Ingwersen, et al.
Clin Pharmacokinet. 2021 Oct;60(10):1335-1348. doi: 10.1007/s40262-021-01025-x. Epub 2021 May 10.
OBJECTIVE: The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials. METHODS: A previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5-10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes. RESULTS: The model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes. CONCLUSIONS: The updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state. CLINICALTRIALS. GOV IDENTIFIERS: NCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.

51A Review on the Efficacy and Safety of Oral Semaglutide.PubMed

Stephanie Niman, Jennifer Hardy, Rebecca F Goldfaden, et al.
Drugs R D. 2021 Jun;21(2):133-148. doi: 10.1007/s40268-021-00341-8. Epub 2021 Mar 26.
There are numerous treatment options currently available for patients with type 2 diabetes mellitus; however, a multitude of patients continue to have inadequately controlled glycemic levels with their current antihyperglycemic regimen. Furthermore, the American Diabetes Association guidelines increasingly highlight the importance of multifactorial management and optimizing medication regimens that include cardiovascular, renal, and/or weight benefits in patients with type 2 diabetes mellitus. Glucagon-like peptide-1 receptor agonists belong to a novel class of type 2 diabetes mellitus agents that are becoming increasingly prevalent owing to their ability to improve glycemic status without the risk of hypoglycemia. Currently, there are three US Food and Drug Administration-approved glucagon-like peptide-1 receptor agonists, subcutaneous semaglutide, dulaglutide, and liraglutide, that also have an indication for reducing major adverse cardiovascular events in patients with type 2 diabetes mellitus and established cardiovascular disease. However, these agents are not often the first options because of their subcutaneous administration. Nevertheless, co-formulation of oral semaglutide with an absorption enhancer has shown to increase its bioavailability and has made its oral absorption possible. In the PIONEER trials, oral semaglutide effectively lowered blood glucose levels, and showed benefits on weight and cardiovascular outcomes; however, there is no Food and Drug Administration indication approved yet as the SOUL trial is still ongoing. Such characteristics of oral semaglutide may improve and increase its use compared to subcutaneous agents and possibly lead to earlier cardiovascular protection in addition to achieving glycemic control.

52Wegovy (semaglutide): a new weight loss drug for chronic weight management.PubMed

Gurdeep Singh, Matthew Krauthamer, Meghan Bjalme-Evans
J Investig Med. 2022 Jan;70(1):5-13. doi: 10.1136/jim-2021-001952. Epub 2021 Oct 27.
Obesity is a growing epidemic within the USA. Because weight gain is associated with an increased risk of developing life-threatening comorbidities, such as hypertension or type 2 diabetes, there is great interest in developing non-invasive pharmacotherapeutics to help combat obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic medications that have shown promise in encouraging glycemic control and promoting weight loss in patients with or without type 2 diabetes. This literature review summarizes and discusses the weight loss results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial programs. The SUSTAIN and PIONEER clinical trials studied the use of 1.0 mg, once-weekly, subcutaneous and oral semaglutide (a new GLP-1 homolog), respectively, on participants with type 2 diabetes. The STEP trial examined the effects of 2.4 mg, once-weekly, subcutaneous semaglutide on patients with obesity. Trial data and other pertinent articles were obtained via database search through the US National Library of Medicine Clinical Trials and the National Center for Biotechnology Information. All three clinical trials demonstrated that semaglutide (injected or oral) has superior efficacy compared with placebo and other antidiabetic medications in weight reduction, which led to Food and Drug Administration approval of Wegovy (semaglutide) for weight loss.

53A Bioequivalence Study of Two Formulations of Oral Semaglutide in Healthy Participants.PubMed

Mette Søndergaard Nielsen, Lise Brøndsted, Martin Kankam, et al.
Diabetes Ther. 2025 Feb;16(2):269-287. doi: 10.1007/s13300-024-01674-8. Epub 2024 Dec 21.
INTRODUCTION: The glucagon-like peptide-1 (GLP-1) analogue semaglutide is approved as an oral formulation for the treatment of type 2 diabetes. This study aimed to confirm bioequivalence between a new, second-generation (2G) oral semaglutide formulation (1.5, 4 and 9 mg) and the initially approved first-generation (1G) formulation (3, 7 and 14 mg). METHODS: This was a randomised, multicentre, open-label, full replicate crossover study to confirm bioequivalence between 2G and 1G oral semaglutide formulations at steady-state (SS) in healthy participants (NCT05227196). Participants were recruited to three groups. In each group, participants were randomised to one of two alternating sequences comparing once-daily oral semaglutide treatment of 9 and 14 mg (group 1), 4 and 7 mg (group 2) or 1.5 and 3 mg (group 3) at SS. Treatment duration was 20 weeks, comprising four 5-week steady-state periods on alternating formulations. Repeated 24-h blood sampling at the end of each steady-state period supported pharmacokinetic analysis. Co-primary endpoints were area under the semaglutide plasma concentration-time curve during a dosing interval at SS (AUC) and maximum semaglutide plasma concentration at SS (C). Bioequivalence for co-primary endpoints was assessed using European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA) criteria. Safety was monitored. RESULTS: A total of 222, 201 and 123 participants were recruited into groups 1, 2 and 3, respectively. The prespecified EMA, FDA and PMDA bioequivalence criteria were met for 2G versus 1G oral semaglutide for all three dose levels (1.5 vs 3 mg, 4 vs 7 mg and 9 vs 14 mg). The safety profile of 2G oral semaglutide was consistent with 1G oral semaglutide. CONCLUSIONS: The 2G oral semaglutide formulation was confirmed as bioequivalent to 1G oral semaglutide, with no new safety concerns identified. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05227196.

54Novel strategy for oral peptide delivery in incretin-based diabetes treatment.PubMed

Yining Xu, Matthias Van Hul, Francesco Suriano, et al.
Gut. 2020 May;69(5):911-919. doi: 10.1136/gutjnl-2019-319146. Epub 2019 Aug 10.
OBJECTIVE: To fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation. DESIGN: We developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice. RESULTS: We demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation. CONCLUSION: We developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.

55Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: Preparation, characterization, and pharmacokinetics.PubMed

Yanan Shi, Miaomiao Yin, Yina Song, et al.
J Biomater Appl. 2021 Feb;35(7):754-761. doi: 10.1177/0885328220947889. Epub 2020 Aug 25.
The delivery of peptides or protein drugs via the oral route has always presented a significant challenge. Here, nanoparticles for the oral delivery of liraglutide are prepared. The nanoparticles are composed of the biodegradable carrier materials chitosan and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA). In addition, CSKSSDYQC (CSK) and hemagglutinin-2 (HA) are introduced into the particles to improve the bioavailability of liraglutide. The size of the nanoparticles is less than 200 nm, and the encapsulation efficiency is approximately 80%. Compared with the subcutaneously injected liraglutide solution group (100%), the relative bioavailability of the nanoparticle group modified with CSK and HA reached 10.12%, which is 2.53 times that of the oral liraglutide solution group. imaging results showed that pHPMA/HA-CSK chitosan nanoparticles (pHPMA/HA-CCNPs) are retained in the gastrointestinal tract for up to 12 h, which is beneficial for oral absorption. CSK and HA modified pHPMA/chitosan nanoparticles significantly improved liraglutide oral bioavailability and therefore have the potential to be applied for oral administration of peptides and proteins.

56Oral administration of zein-based nanoparticles reduces glycemia and improves glucose tolerance in rats.PubMed

Cristian Reboredo, Carlos J González-Navarro, Ana L Martínez-López, et al.
Int J Pharm. 2022 Nov 25;628:122255. doi: 10.1016/j.ijpharm.2022.122255. Epub 2022 Sep 30.
The aim was to evaluate the effect of zein-based nanoparticles on the glucose homeostasis, following oral administration to Wistar rats. For this purpose, bare nanoparticles (NP, with tropism for the upper intestinal regions) and poly(ethylene glycol)-coated nanoparticles (NP-PEG), with the capability to reach the ileum and cecum of animals, were evaluated. Both formulations were spherical in shape, displaying sizes around 200 nm and a negative surface zeta potential. The oral administration of a single dose of these nanoparticles to animals (50 mg/kg) induced a significant decrease of the glycemia, compared control rats and in animals treated with the free protein (p < 0.001). Moreover, these nanoparticles improved the glycemic control against an intraperitoneal glucose tolerance test; particularly NP-PEG. These findings would be due to an increased release of glucagon-like peptide-1 (GLP-1) by l-cells, which are more abundant in distal regions of the intestine. In fact, the GLP-1 blood levels of animals treated with nanoparticles were significantly higher than controls (about 40 % and 60 % for NP and NP-PEG groups, respectively). This higher capability of NP-PEG, with respect to NP, to increase the release of GLP-1 and control glycemia would be related to its ability to reach the distal areas of the small intestine.

57Strategies for Appropriate Selection of SGLT2-i vs. GLP1-RA in Persons with Diabetes and Cardiovascular Disease.PubMed

Devinder S Dhindsa, Anurag Mehta, Pratik B Sandesara, et al.
Curr Cardiol Rep. 2019 Jul 27;21(9):100. doi: 10.1007/s11886-019-1197-6.
PURPOSE OF REVIEW: This review will serve to highlight the clinical rationale used in the selection of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) or glucagon-like peptide 1 receptor agonists (GLP1-ra). RECENT FINDINGS: SGLT2-i and GLP1-ra are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit in multiple cardiovascular outcomes trials (CVOTs), with benefits that are consistent across class of medication. Diabetes is a major risk factor for morbidity and mortality from cardiovascular disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and glucagon-like peptide 1 receptor agonists (GLP1-ra) are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit. Given the unique side effect and benefit profiles, appropriate consideration of these agents with a focus on cardiovascular risk reduction requires an individualized approach.

58Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor.PubMed

Ralph A DeFronzo
Diabetes Obes Metab. 2017 Oct;19(10):1353-1362. doi: 10.1111/dom.12982. Epub 2017 Jun 7.
The SGLT2 inhibitors (SGLTi) and glucagon-like-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP-1 RAs work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits. The SGLT2i and GLP-1 RAs also reduced macroalbuminuria, decreased the time for doubling of serum creatinine, and slowed the time to end-stage renal disease. In this perspective, we review the potential benefit of combination SGLT2i/GLP-1 RA therapy on metabolic-cardiovascular-renal disease in patients with type 2 diabetes mellitus.

59Cardiovascular, Kidney, and Safety Outcomes With GLP-1 Receptor Agonists Alone and in Combination With SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.PubMed

Brendon L Neuen, Robert A Fletcher, Lauren Heath, et al.
Circulation. 2024 Nov 26;150(22):1781-1790. doi: 10.1161/CIRCULATIONAHA.124.071689. Epub 2024 Aug 30.
BACKGROUND: GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter 2) inhibitors both improve cardiovascular and kidney outcomes in people with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. METHODS: We searched MEDLINE and Embase databases from inception until July 12, 2024, for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance-weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50% reduction in estimated glomerular filtration rate, kidney failure or death caused by kidney failure, and annualized rate of decline in estimated glomerular filtration rate (estimated glomerular filtration rate slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024565765). RESULTS: We identified 3 trials with 1743 of 17 072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (hazard ratio [HR], 0.79 [95% CI, 0.71-0.87]), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77 [95% CI, 0.54-1.09] and HR, 0.79 [95% CI, 0.71-0.87], respectively; -heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR, 0.58 [95% CI, 0.36-0.93] and HR, 0.73 [95% CI, 0.63-0.85]; -heterogeneity=0.26). Effects on the composite kidney outcome (risk ratio, 0.79 [95% CI, 0.66-0.95]) and estimated glomerular filtration rate slope (0.78 mL/min/1.73 m/y [95% CI, 0.57-0.98]) also did not vary according to SGLT2 inhibitor use (-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (-heterogeneity=0.29 and 0.50, respectively). CONCLUSIONS: In people with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

60Effect of combination treatment with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on incidence of cardiovascular and serious renal events: population based cohort study.PubMed

Nikita Simms-Williams, Nir Treves, Hui Yin, et al.
BMJ. 2024 Apr 25;385:e078242. doi: 10.1136/bmj-2023-078242.
OBJECTIVE: To determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal events compared with either drug class alone among patients with type 2 diabetes, and to assess the effect of the combination on the individual components of major adverse cardiovascular events, heart failure, and all cause mortality. DESIGN: Population based cohort study using a prevalent new-user design, emulating a trial. SETTING: UK Clinical Practice Research Datalink linked to Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases. PARTICIPANTS: Two prevalent new-user cohorts were assembled between January 2013 and December 2020, with follow-up until the end of March 2021. The first cohort included 6696 patients who started GLP-1 receptor agonists and added on SGLT-2 inhibitors, and the second included 8942 patients who started SGLT-2 inhibitors and added on GLP-1 receptor agonists. Combination users were matched, in a 1:1 ratio, to patients prescribed the same background drug, duration of background drug, and time conditional propensity score. MAIN OUTCOME MEASURES: Cox proportional hazards models were fitted to estimate the hazard ratios and 95% confidence intervals of major adverse cardiovascular events and serious renal events, separately, comparing the GLP-1 receptor agonist-SGLT-2 inhibitor combination with the background drug, either GLP-1 receptor agonists or SGLT-2 inhibitors, depending on the cohort. Secondary outcomes included associations with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality. RESULTS: Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41). Secondary outcomes generated similar results but with wider confidence intervals. CONCLUSIONS: In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.

61Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial.PubMed

Bernard Zinman, Vaishali Bhosekar, Robert Busch, et al.
Lancet Diabetes Endocrinol. 2019 May;7(5):356-367. doi: 10.1016/S2213-8587(19)30066-X. Epub 2019 Mar 1.
BACKGROUND: Semaglutide is a once-weekly glucagon-like peptide-1 (GLP-1) analogue for type 2 diabetes. Few clinical trials have reported on the concomitant use of GLP-1 receptor agonists with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We aimed to investigate the efficacy and safety of semaglutide when added to SGLT-2 inhibitor therapy in patients with inadequately controlled type 2 diabetes. METHODS: The SUSTAIN 9 double-blind, parallel-group trial was done at 61 centres in six countries (Austria, Canada, Japan, Norway, Russia, and the USA). Adults with type 2 diabetes and HbA 7·0-10·0% (53-86 mmol/mol), despite at least 90 days of treatment with an SGLT-2 inhibitor, were randomly assigned (1:1) to receive subcutaneous semaglutide 1·0 mg or volume-matched placebo once weekly for 30 weeks, after a dose-escalation schedule of 4 weeks of 0·25 mg semaglutide or placebo and 4 weeks of 0·5 mg semaglutide or placebo. Existing antidiabetic medications, including SGLT-2 inhibitor treatment, were continued for the duration of the trial. Rescue medication, defined as intensification of background antidiabetic treatment or the initiation of new glucose-lowering medications, could be given to patients meeting specific criteria at the discretion of the investigator. The primary outcome was change in HbA from baseline at week 30, assessed in the full analysis set (all patients randomly allocated to treatment) using on-treatment data collected before rescue medication was started. The confirmatory secondary outcome was change in bodyweight from baseline to week 30. Safety was also assessed in the safety analysis set (all patients who received at least one dose of treatment). The trial was registered with ClinicalTrials.gov (NCT03086330). FINDINGS: Between March 15, and Dec 4, 2017, 302 patients were enrolled and randomly assigned to receive semaglutide 1·0 mg or placebo (full analysis set), of whom 301 received at least one dose of treatment (safety analysis set). One patient was assigned to semaglutide but was not treated (reason unknown). 294 (97·4%) patients completed the trial and 267 (88·4%) completed treatment. Baseline characteristics were generally comparable between groups. In addition to randomised medication and SGLT-2 inhibitor, 216 (71·5%) patients were taking metformin and 39 (12·9%) were taking sulphonylurea. Patients given semaglutide had greater reductions in HbA (estimated treatment difference -1·42% [95% CI -1·61 to -1·24]; -15·55 mmol/mol [-17·54 to -13·56]) and bodyweight (-3·81 kg [-4·70 to -2·93]) versus those randomised to placebo (both p<0·0001). 356 adverse events were reported by 104 (69·3%) patients in the semaglutide group, and 247 adverse events were reported by 91 (60·3%) patients in the placebo group. Gastrointestinal adverse events were most common and were reported in 56 (37·3%) patients in the semaglutide group and 20 (13·2%) in the placebo group. Serious adverse events occurred in seven (4·7%) patients in the semaglutide group and six (4·0%) in the placebo group. Severe or blood glucose-confirmed hypoglycaemic events were reported in four patients on semaglutide (2·7%). 16 patients stopped treatment early because of an adverse event, 13 of whom were in the semaglutide group. There were no deaths during the trial. INTERPRETATION: Adding semaglutide to SGLT-2 inhibitor therapy significantly improves glycaemic control and reduces bodyweight in patients with inadequately controlled type 2 diabetes, and is generally well tolerated. FUNDING: Novo Nordisk.

62Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial.PubMed

Johannes F E Mann, Peter Rossing, George Bakris, et al.
Nat Med. 2024 Oct;30(10):2849-2856. doi: 10.1038/s41591-024-03133-0. Epub 2024 Jun 24.
People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P < 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min/1.73 m/year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use (P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 .

63Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial.PubMed

Nikolaus Marx, John E Deanfield, Johannes F E Mann, et al.
Circulation. 2025 Jun 10;151(23):1639-1650. doi: 10.1161/CIRCULATIONAHA.125.074545. Epub 2025 Mar 29.
BACKGROUND: Both GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter-2) inhibitors (SGLT2i) improve cardiovascular outcomes in people with type 2 diabetes and cardiovascular or chronic kidney disease. However, there are limited data about the effect of combining these agents on cardiovascular and safety outcomes. METHODS: The SOUL trial (Semaglutide Cardiovascular Outcomes Trial; NCT03914326) randomized 9650 participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease to oral semaglutide or placebo. As prespecified, participants were analyzed according to baseline use of SGLT2i (yes, n=2596; no, n=7054), and subsequently for any use of SGLT2i during the trial (yes, n=4718; no, n=4932). The primary outcome was time to first major adverse cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Safety was evaluated by comparing the incidence of serious adverse events. RESULTS: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide versus placebo (hazard ratio, 0.86; 95% CI, 0.77-0.96). In those taking SGLT2i at baseline, there were 143 of 1296 (semaglutide) versus 158 of 1300 (placebo) primary outcome events (hazard ratio, 0.89; 95% CI, 0.71-1.11); and 436 of 3529 versus 510 of 3525, respectively, in participants not taking SGLT2i at baseline (hazard ratio, 0.84; 95% CI, 0.74-0.95; -interaction, 0.66). An analysis of major adverse cardiovascular events by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar. CONCLUSIONS: Oral semaglutide reduced major adverse cardiovascular event outcomes independently of concomitant SGLT2i treatment, and this combination appeared to be safe. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03914326.

64Weight management treatment in obesity.PubMed

Miguel A Rubio-Herrera, Sara Mera-Carreiro
Med Clin (Barc). 2025 Nov;165(5):107152. doi: 10.1016/j.medcli.2025.107152. Epub 2025 Aug 26.
Obesity is a chronic and relapsing disease associated with medical complications and mortality. Our improved understanding of the relevance of the gut-brain axis in regulating appetite and body weight has encouraged research into nutrient-stimulated gastroenteropancreatic hormones as a new therapeutic arsenal for the treatment of people living with obesity. Beyond the necessary lifestyle changes, this new era with second-generation drugs has been able to achieve weight loss of 15-25%, close to that of bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists (RA), used as weekly injectable monotherapy or daily oral (semaglutide), achieve weight loss of 15-17%, with a good safety profile. The synergistic combination with other hormones (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, or amylin) will allow to increase weight loss, as well as improve cardiometabolic variables. Tirzepatide (a dual GLP-1/GIP receptor agonist) achieves weight loss of up to 22.5% at the highest doses. In this same range of weight loss, it is expected that it can be achieved with the combination of Cagrisema (cagrilintide 2.4mg plus semaglutide 2.4mg), combinations of GLP-1 RAs - glucagon agonists or with the triple combination of GLP-1 RAs-GIP-Glucagon (Retatrutide). In this review, we will examine the efficacy and safety of the drugs marketed and others under ongoing clinical trials for the treatment of persons with obesity, as well as the main challenges faced by both healthcare professionals and patients in maintaining long-term treatment.

65Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial.PubMed

Lone B Enebo, Kasper K Berthelsen, Martin Kankam, et al.
Lancet. 2021 May 8;397(10286):1736-1748. doi: 10.1016/S0140-6736(21)00845-X. Epub 2021 Apr 22.
BACKGROUND: Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. METHODS: In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18-55 years with a body-mass index 27·0-39·9 kg/m and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC) and maximum concentration [C] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to C [t], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. FINDINGS: Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16-2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16-4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC ranged from 926 nmol × h/L to 24 271 nmol × h/L, and C ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16-4·5 mg. AUC ranged from 12 757 nmol × h/L to 15 305 nmol × h/L, and C ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·16-4·5 mg had a half-life of 159-195 h, with a median t of 24-72 h. Semaglutide 2·4 mg had a half-life of 145-165 h, with a median t of 12-24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1-5; estimated treatment difference of -6·0% [95% CI -9·9 to -2·0] for cagrilintide 1·2 mg and -7·4% [-11·2 to -3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference -7·4% [-12·8 to -2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. INTERPRETATION: Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. FUNDING: Novo Nordisk A/S.

66Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.PubMed

Stefano Ciardullo, Emanuele Muraca, Michela Vergani, et al.
Gastroenterol Rep (Oxf). 2024 Apr 26;12:goae029. doi: 10.1093/gastro/goae029. eCollection 2024.
In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

67Current status and future perspectives of FGF21 analogues in clinical trials.PubMed

Zara Siu Wa Chui, Qing Shen, Aimin Xu
Trends Endocrinol Metab. 2024 May;35(5):371-384. doi: 10.1016/j.tem.2024.02.001. Epub 2024 Feb 28.
Recent advances in fibroblast growth factor 21 (FGF21) biology and pharmacology have led to the development of several long-acting FGF21 analogues and antibody-based mimetics now in various phases of clinical trials for the treatment of obesity-related metabolic comorbidities. The efficacy of these FGF21 analogues/mimetics on glycaemic control and weight loss is rather mild and inconsistent; nevertheless, several promising therapeutic benefits have been reproducibly observed in most clinical studies, including amelioration of dyslipidaemia (particularly hypertriglyceridaemia) and hepatic steatosis, reduction of biomarkers of liver fibrosis and injury, and resolution of metabolic dysfunction-associated steatohepatitis (MASH). Evidence is emerging that combination therapy with FGF21 analogues and other hormones (such as glucagon-like peptide 1; GLP-1) can synergise their pharmacological benefits, thus maximising the therapeutic efficacy for obesity and its comorbidities.

68Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective.PubMed

Christophe De Block, Clifford Bailey, Carol Wysham, et al.
Diabetes Obes Metab. 2023 Jan;25(1):3-17. doi: 10.1111/dom.14831. Epub 2022 Aug 31.
Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (-1.87 to -2.59%, -20 to -28 mmol/mol) and body weight (-6.2 to -12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

69Combination therapy for kidney disease in people with diabetes mellitus.PubMed

Daniël H van Raalte, Petter Bjornstad, David Z I Cherney, et al.
Nat Rev Nephrol. 2024 Jul;20(7):433-446. doi: 10.1038/s41581-024-00827-z. Epub 2024 Apr 3.
Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20-40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin-angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.

70Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists.PubMed

Hellas Cena, Luca Chiovato, Rossella E Nappi
J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695-709. doi: 10.1210/clinem/dgaa285.
CONTEXT: Obesity is responsible for an increased risk of sub-fecundity and infertility. Obese women show poorer reproductive outcomes regardless of the mode of conception, and higher body mass index (BMI) is associated with poorer fertility prognosis. Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility, and many women with PCOS are also overweight or obese. EVIDENCE ACQUISITION: The aim of the present narrative review is to describe the mechanisms responsible for the development of infertility and PCOS in women with obesity/overweight, with a focus on the emerging role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) as a therapeutic option for obese women with PCOS. EVIDENCE SYNTHESIS: Weight reduction represents the most significant factor affecting fertility and pregnancy outcomes. Current experimental and clinical evidence suggests the presence of an underlying pathophysiological link between obesity, GLP-1 kinetic alterations, and PCOS pathogenesis. Based on the positive results in patients affected by obesity, with or without diabetes, the administration of GLP-1 RA (mainly liraglutide) alone or in combination with metformin has been investigated in women with obesity and PCOS. Several studies demonstrated significant weight loss and testosterone reduction, with mixed results relative to improvements in insulin resistance parameters and menstrual patterns. CONCLUSIONS: The weight loss effects of GLP-1 RA offer a unique opportunity to expand the treatment options available to PCOS patients.

71GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis.PubMed

Yi Han, Yingjie Li, Bing He
Reprod Biomed Online. 2019 Aug;39(2):332-342. doi: 10.1016/j.rbmo.2019.04.017. Epub 2019 Apr 25.
This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide 1 (GLP-1) receptor agonists for women with polycystic ovary syndrome (PCOS) by comparing their effect with that of metformin. Electronic databases (PubMed, EMBASE, Cochrane Library, WanFang Database, CNKI) dating from their establishment to June 2018 were searched to find all randomized controlled trials (RCTs) reporting the efficacy of GLP-1 receptor agonists versus metformin for patients with PCOS. Therapeutic variables included menstrual cycle, sex hormone and clinical manifestations, glucose metabolism and other metabolic indexes. Eight RCTs among 462 related articles were included in the meta-analysis. Compared with metformin, GLP-1 receptor agonists were more effective in improving insulin sensitivity (standard mean difference [SMD] -0.40, 95% confidence interval [CI] -0.74 to -0.06, P = 0.02) and reducing body mass index (SMD -1.02, 95% CI -1.85 to -0.19, P = 0.02) and abdominal girth (SMD -0.45, 95% CI -0.89 to -0.00, P = 0.05). GLP-1 receptor agonists were associated with a higher incidence of nausea and headache than metformin, but there were no significant differences in other data. Therefore, compared with metformin, GLP-1 receptor agonists might be a good choice for obese patients with PCOS, especially those with insulin resistance. The available evidence is, however, inconclusive given its moderate to low quality. More high-quality research is needed to assess the efficacy of a GLP-1 receptor agonist on women with PCOS.

72Pharmacotherapy for chronic obesity management: a look into the future.PubMed

Mariana Abdel-Malek, Lisa Yang, Alexander Dimitri Miras
Intern Emerg Med. 2023 Jun;18(4):1019-1030. doi: 10.1007/s11739-023-03237-4. Epub 2023 May 30.
Substantial leaps have been made in the drug discovery front in tackling the growing pandemic of obesity and its metabolic co-morbidities. Greater mechanistic insight and understanding of the gut-brain molecular pathways at play have enabled the pursuit of novel therapeutic agents that possess increasingly efficacious weight-lowering potential whilst remaining safe and tolerable for clinical use. In the wake of glucagon-like peptide 1 (GLP-1) based therapy, we look at recent advances in gut hormone biology that have fermented the development of next generation pharmacotherapy in diabesity that harness synergistic potential. In this paper, we review the latest data from the SURPASS and SURMOUNT clinical trials for the novel 'twincretin', known as Tirzepatide, which has demonstrated sizeable body weight reduction as well as glycaemic efficacy. We also provide an overview of amylin-based combination strategies and other emerging therapies in the pipeline that are similarly providing great promise for the future of chronic management of obesity.

73Paradigm shift in obesity treatment: an extensive review of current pipeline agents.PubMed

Ecesu Çetin, Brian Pedersen, Mehmet Furkan Burak
Turk J Med Sci. 2025 Jan 15;55(1):1-16. doi: 10.55730/1300-0144.5938. eCollection 2025.
Obesity is a multifaceted disease that poses a significant public health challenge. Recent discoveries in understanding the biological pathways that regulate satiety and metabolism have led to a shift in the treatment paradigm for obesity. Thus, the gap between pharmacological and surgical interventions has diminished. The latest approved antiobesity medications help to achieve weight loss comparable to surgery. These GLP-1 analog-based therapies not only cause substantial weight loss but also improve obesity-associated comorbidities. However, there are still unmet needs in obesity care, and treatment options with alternative pathways are necessary. Whether achieved through lifestyle changes or medication, weight loss often leads to muscle mass loss and reduced energy expenditure, resulting in rebound weight gain. Moreover, addressing severe obesity and comorbidities, such as metabolic-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH), heart failure with preserved ejection fraction, and obstructive sleep apnea, necessitates the development of additional therapeutic strategies. Various antiobesity medications with novel mechanisms of action are currently in the pipeline. Myostatin-activin pathway inhibitors are under development to preserve muscle mass, and combination therapies with glucagon agonists address MAFLD and MASH. Amylin agonists offer a promising alternative to those unable to tolerate GLP-1 analogs. Mitochondrial uncouplers are under investigation for enhancing energy expenditure, NLRP-3 inhibitors for reducing inflammation, and GWAS targets for additional weight loss benefits. Combination therapies, such as dual or triple hormonal receptor agonists, are being developed to maximize weight loss and optimize tolerability. These emerging medications in the clinical trial pipeline show promise for more tolerable and sustainable obesity management.

74Emerging pharmacotherapies for obesity: A systematic review.PubMed

Michail Kokkorakis, Marlene Chakhtoura, Caline Rhayem, et al.
Pharmacol Rev. 2025 Jan;77(1):100002. doi: 10.1124/pharmrev.123.001045. Epub 2024 Nov 22.
The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

75What is the pipeline for future medications for obesity?PubMed

Eka Melson, Uzma Ashraf, Dimitris Papamargaritis, et al.
Int J Obes (Lond). 2025 Mar;49(3):433-451. doi: 10.1038/s41366-024-01473-y. Epub 2024 Feb 1.
Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

76GLP-1 physiology informs the pharmacotherapy of obesity.PubMed

Daniel J Drucker
Mol Metab. 2022 Mar;57:101351. doi: 10.1016/j.molmet.2021.101351. Epub 2021 Oct 6.
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity. SCOPE OF REVIEW: Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted. MAJOR CONCLUSIONS: The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.

77G protein-coupled receptors and obesity.PubMed

Alessandro Pocai
Front Endocrinol (Lausanne). 2023 Dec 14;14:1301017. doi: 10.3389/fendo.2023.1301017. eCollection 2023.
G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.

78GLP-1 Receptor Agonists.PubMed

Clifford J Rosen, Julie R Ingelfinger
N Engl J Med. 2026 Apr 2;394(13):1313-1324. doi: 10.1056/NEJMra2500106.
Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin analogues that promote glucose-mediated insulin release and are used to treat type 2 diabetes mellitus and obesity. GLP-1 receptor agonists and GLP-1 and glucose-dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety (which promotes weight loss). Beyond the impressive effects of GLP-1 receptor agonists on blood glucose levels and body weight, large-scale randomized, controlled trials have shown that GLP-1 receptor agonists reduce cardiovascular risk and slow progression to renal failure in persons at high risk and those with type 2 diabetes. Adverse side effects from GLP-1 receptor agonists are mostly gastrointestinal but may also include loss of muscle and bone mass. Questions remain about long-term adherence, weight regain after discontinuation of treatment, and the functional implications of the loss of muscle and bone mass. Recent and ongoing targeted studies suggest the possibility of additional uses for GLP-1 receptor agonists.

79User's guide to mechanism of action and clinical use of GLP-1 receptor agonists.PubMed

Charles F Shaefer, Pamela Kushner, Richard Aguilar
Postgrad Med. 2015;127(8):818-26. doi: 10.1080/00325481.2015.1090295. Epub 2015 Sep 15.
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release-responses that are both glucose-dependent-with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.

80A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.PubMed

Philip N Newsome, Kristine Buchholtz, Kenneth Cusi, et al.
N Engl J Med. 2021 Mar 25;384(12):1113-1124. doi: 10.1056/NEJMoa2028395. Epub 2020 Nov 13.
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. CONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

81Safety of Semaglutide.PubMed

Mark M Smits, Daniël H Van Raalte
Front Endocrinol (Lausanne). 2021 Jul 7;12:645563. doi: 10.3389/fendo.2021.645563. eCollection 2021.
The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

82Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.PubMed

Matthew James Armstrong, Piers Gaunt, Guruprasad P Aithal, et al.
Lancet. 2016 Feb 13;387(10019):679-690. doi: 10.1016/S0140-6736(15)00803-X. Epub 2015 Nov 20.
BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS: This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING: Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

83Adverse Effects of GLP-1 Receptor Agonists.PubMed

Theodosios D Filippatos, Thalia V Panagiotopoulou, Moses S Elisaf
Rev Diabet Stud. 2014 Fall-Winter;11(3-4):202-30. doi: 10.1900/RDS.2014.11.202. Epub 2015 Feb 10.
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.

84Glucagon-Like Peptide-1 Receptor Agonists and Risk of Neovascular Age-Related Macular Degeneration.PubMed

Reut Shor, Andrew Mihalache, Atefeh Noori, et al.
JAMA Ophthalmol. 2025 Jul 1;143(7):587-594. doi: 10.1001/jamaophthalmol.2025.1455.
IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are extensively used in treating diabetes and obesity, yet little is known about the long-term ocular effects of systemic prolonged exposure. OBJECTIVE: To evaluate the risk of developing neovascular age-related macular degeneration (nAMD) associated with the use of GLP-1 RAs in patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: This population-based, retrospective cohort study was conducted from January 2020 to November 2023, with a follow-up period of 3 years. Data analysis was performed from August 2024 to October 2024. The investigators used comprehensive administrative health and demographic data from patients in Ontario, Canada, which were collected by the Institute for Clinical Evaluative Sciences in the context of a universal public health care system. Inclusion criteria were patients aged 66 years or older with a diagnosis of diabetes and a minimum follow-up period of 12 months following initial diabetes diagnosis. Patients with incomplete Ontario Health Insurance Plan or Ontario Drug Benefit data or patients exposed to GLP-1 RA for less than 6 months were excluded. Of 1 119 517 eligible patients, a 1:2 matched cohort of 139 002 patients was created, including 46 334 patients who were exposed to GLP-1 RAs and 92 668 unexposed matched patients. Systemic comorbidities that were associated with any kind of AMD and socioeconomic status were used to calculate propensity scores. EXPOSURE: GLP-1 RA use for 6 months or longer. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence and time to event of nAMD during the follow-up period. RESULTS: Among 139 002 matched patients, mean (SD) patient age was 66.2 (7.5) years, and 64 775 patients (46.6%) were women. The incidence of nAMD was higher among the exposed cohort than among the unexposed cohort. Cox proportional hazard models, both unadjusted (crude) and adjusted, estimated hazard ratios for nAMD development of greater than 2.0 among patients exposed to GLP-1 RAs (exposed, 0.2% vs unexposed, 0.1%; difference, 0.1%; crude: HR, 2.11; 95% CI, 1.58-2.82; adjusted: HR, 2.21; 95% CI, 1.65-2.96). CONCLUSIONS AND RELEVANCE: In this cohort study, the use of GLP-1 RAs among patients with diabetes was associated with a 2-fold higher risk of incident nAMD development than among similar patients with diabetes who did not receive a GLP-1 RA. Further research is needed to elucidate the exact pathophysiological mechanisms involved and to understand the trade-offs between the benefits and risks of GLP-1 RAs.

85GLP-1 Receptor Agonists and Cancer Risk in Adults With Obesity.PubMed

Hao Dai, Yongqiu Li, Yao An Lee, et al.
JAMA Oncol. 2025 Oct 1;11(10):1186-1193. doi: 10.1001/jamaoncol.2025.2681.
IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely prescribed for glycemic control in type 2 diabetes and have recently gained popularity for weight management. However, their long-term impact on cancer risk remains uncertain. Understanding this association is crucial for patient safety. OBJECTIVE: To compare the incidence of 14 cancers among adults with obesity prescribed GLP-1RAs vs nonusers. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study followed a target trial emulation design using 2014 to 2024 electronic health record data from OneFlorida+, a multicenter health research network that integrates real-world clinical data from diverse health care settings. Adults 18 years or older eligible for antiobesity medications without prior cancer history were included. Participants were categorized as GLP-1RA users or nonusers, matched 1:1 using propensity scores. EXPOSURE: Individuals taking vs not taking GLP-1RAs. MAIN OUTCOMES AND MEASURES: The primary outcomes were the incidence of 14 cancer types, including 13 obesity-associated cancers (liver, thyroid, pancreatic, bladder, colorectal, kidney, breast, endometrial, meningioma, upper gastrointestinal, ovarian, multiple myeloma, and prostate) and lung cancer. RESULTS: A total of 86 632 matched adults (mean [SD] age, 52.4 [14.5] years; 68.2% female) were included, comprising 43 317 GLP-1RA users and 43 315 otherwise eligible nonusers. The incidence rates of the 14 cancers were 13.6 vs 16.4 per 1000 person-years, respectively, indicating a significantly lower overall cancer risk among individuals taking GLP-1RAs (hazard ratio [HR], 0.83 [95% CI, 0.76-0.91]; P = .002) compared with nonusers. In particular, taking GLP-1RAs was associated with a reduced risk of endometrial cancer (HR, 0.75 [95% CI, 0.57-0.99]; P = .05), ovarian cancer (HR, 0.53 [95% CI, 0.29-0.96]; P = .04), and meningioma (HR, 0.69 [95% CI, 0.48-0.97]; P = .05). However, GLP-1RAs were associated with a marginally nonsignificant increased risk of kidney cancer (HR, 1.38 [95% CI, 0.99-1.93]; P = .04). CONCLUSIONS AND RELEVANCE: This retrospective cohort study found that taking GLP-1RAs was associated with a reduced overall risk of cancer, including lower risks of endometrial, ovarian, and meningioma cancers, among patients with obesity or overweight. However, taking GLP-1RAs may be associated with an increased risk of kidney cancer, highlighting the need for longer-term follow-up to clarify the underlying mechanisms and clinical implications of these findings.

86Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials.PubMed

Yuming Sun, Yongjia Liu, Yating Dian, et al.
Int J Surg. 2024 Aug 1;110(8):4688-4694. doi: 10.1097/JS9.0000000000001514.
BACKGROUND: Glucagon-like peptide-1 receptor (GLP1R) agonists have been approved by Food and Drug Administration for management of obesity. However, the causal relationship of GLP1R agonists (GLP1RA) with cancers still unclear. METHODS: The available cis-eQTLs for drugs target genes (GLP1R) were used as proxies for exposure to GLP1RA. Mendelian randomizations (MR) were performed to reveal the association of genetically-proxied GLP1RA with 14 common types cancer from large-scale consortia. Type 2 diabetes was used as positive control, and the GWASs data including 80 154 cases and 853 816 controls. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, all the related randomized controlled trails (RCTs) on GLP1RA were systematically searched from PubMed, Embase, and the Cochrane Library to comprehensively synthesize the evidence to validate any possible association with cancers. RESULT: A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instrument. The association of genetically-proxied GLP1RA with significantly decreased type 2 diabetes risk [OR (95%)=0.82 (0.79-0.86), P <0.001], which ensuring the effectiveness of identified genetic instruments. The authors found favorable evidence to support the association of GLP1RA with reduced breast cancer and basal cell carcinoma risk [0.92 (0.88-0.96), P <0.001, 0.92 (0.85-0.99), P =0.029, respectively], and with increased colorectal cancer risk [1.12 (1.07-1.18), P <0.001]. In addition, there was no suggestive evidence to support the association of GLP1RA with ovarian cancer [0.99 (0.90-1.09), P =0.827], lung cancer [1.01 (0.93-1.10), P =0760], and thyroid cancer [0.83 (0.63-1.10), P =0.187]. Our findings were consistent with the meta-analysis. Finally, 80 RCTs were included in the systematic review, with a low incidence of different kinds of cancer. CONCLUSIONS: Our study suggests that GLP1RA may decrease the risk of breast cancer and basal cell carcinoma, but increase the risk of colorectal cancer. However, according to the systematic review of RCTs, the incidence of cancer in patients treated with GLP1RA is low. Larger sample sizes of RCTs with long-term follow-up are necessary to establish the incidence of cancers and evaluate the risk-benefit ratios.

87Weight Regain After GLP-1-Based Therapy Discontinuation: Failure, Physiology, or Follow-Up Gap.PubMed

Andres F Quimbayo-Cifuentes
Cureus. 2026 Feb 25;18(2):e104259. doi: 10.7759/cureus.104259. eCollection 2026 Feb.
The introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin agonists targeting both the GIP and GLP-1 receptors (GIP/GLP-1 dual agonists) has reshaped obesity management, approaching degrees of weight loss previously achievable largely through metabolic surgery. However, randomized withdrawal trials, including Semaglutide Treatment Effect in People with Obesity (STEP) 4 and SURMOUNT 4, show that discontinuation of GLP-1-based therapy is consistently followed by rapid weight regain (typically observed within one year of withdrawal) and a decline in cardiometabolic benefits. Rather than indicating therapeutic failure, this pattern is best understood as disease recurrence, reinforcing obesity as a chronic, relapsing condition. After treatment is discontinued, homeostatic weight-defense mechanisms re-emerge, favoring a return toward the pre-treatment set point. This editorial examines the biology underpinning post-discontinuation weight regain and highlights a clinically underappreciated consequence: sarcopenic obesity, driven by preferential fat mass recovery relative to lean mass. It also discusses mitigation strategies, including resistance training and structured tapering approaches, and argues for long-term, maintenance-oriented care as an ethical imperative in chronic obesity management.

88Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis.PubMed

Sara Berg, Hannah Stickle, Suzanne J Rose, et al.
Obes Rev. 2025 Aug;26(8):e13929. doi: 10.1111/obr.13929. Epub 2025 Apr 4.
Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text, Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy. PRACTITIONER POINTS: Question: Does discontinuation of Glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment lead to significant weight gain? Findings: In this systematic review and meta-analysis, discontinuing GLP-1RA treatment led to a pooled overall mean weight regain of 2.20 kg in participants taking liraglutide and 9.69 kg in those patients prescribed semaglutide/tirzepatide. The proportion of weight regained was proportional to the amount originally lost. Meaning: Discontinuation of GLP-1RA treatment leads to weight regain, regardless of lifestyle interventions, and should therefore be considered a chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity.

89Effects of Glucagon-Like Peptide-1 Receptor Agonists After Treatment Withdrawal: A Systematic Review and Meta-Analysis.PubMed

Lei Zhou, Aiming Wei, Chongsheng Pan, et al.
J Gen Intern Med. 2026 Feb;41(3):807-818. doi: 10.1007/s11606-025-09950-4. Epub 2025 Nov 17.
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively promote weight reduction and improve glycemic control, blood pressure, and lipid profiles in individuals with overweight or obesity. This systematic review and meta-analysis evaluates the durability of these therapeutic benefits following treatment discontinuation. METHODS: We conducted a systematic search of PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP from inception to June 2024, to identify randomized controlled trials that assessed the effects of GLP-1RAs with a follow-up period of at least six months after treatment discontinuation. The outcomes were changes in weight, body mass index (BMI), waist circumference (WC), glycemia, blood pressure, and lipid profiles. RESULTS: We screened 10,670 studies and ultimately identified 5 eligible studies, encompassing 719 patients. Compared to the control group, GLP-1RAs were associated with significant reductions in weight (mean difference (MD) = -5.70 kg, 95% confidence interval (CI): -9.52 to -1.88), BMI (MD = -2.94 kg/m, 95% CI: -5.60 to -0.28), WC (MD = -3.66 cm, 95% CI: -4.89 to -2.43), glycated hemoglobin A1c (HbA1c) (standardized mean difference (SMD) = -0.73, 95% CI: -1.14 to -0.32), and systolic blood pressure (SBP) (MD = -3.62 mm Hg, 95% CI: -5.51 to -1.73) after cessation of therapy. After discontinuation, there was a pronounced rebound in weight (MD = 4.13 kg, 95% CI: 1.60 to 6.65), BMI (MD = 0.84 kg/m, 95% CI: 0.37 to 1.32), WC (MD = 3.64 cm, 95% CI: 2.27 to 5.01), and HbA1c (SMD = 0.69, 95% CI: 0.50 to 0.89). From study baseline to the end of follow-up, GLP-1RAs treatment resulted in statistically significant decreases in weight (MD = -2.32 kg, 95% CI: -4.21 to -0.43) and BMI (MD = -0.82 kg/m, 95% CI: -1.47 to -0.17). CONCLUSIONS: This meta-analysis demonstrated that although statistically significant weight reduction persists after GLP-1RAs discontinuation, the clinical significance and durability of this effect are limited. To achieve sustained therapeutic benefits, continued treatment with these agents may be necessary.

90A Comprehensive Review on Weight Gain following Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists for Obesity.PubMed

Ibrahim Abdullah Bin Ahmed
J Obes. 2024 May 10;2024:8056440. doi: 10.1155/2024/8056440. eCollection 2024.
Obesity is considered the leading public health problem in the medical sector. The phenotype includes overweight conditions that lead to several other comorbidities that drastically decrease health. Glucagon-like receptor agonists (GLP-1RAs) initially designed for treating type 2 diabetes mellitus (T2DM) had demonstrated weight loss benefits in several clinical trials studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. Additionally, GLP-1RAs were found to regulate food intake through stimulation of sensory neurons in the vagus, interaction with the hypothalamus and hindbrain, and through inflammation and intestinal microbiota. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. We could identify three different ways that could lead to weight gain. Potential factors might include temporary hormonal adjustment in response to weight reduction, the central nervous system's (CNS) incompetence in regulating weight augmentation owing to the lack of GLP-1RA, and -cell malfunction due to sustained exposure to GLP-1RA. Here, we also review the data from clinical studies that reported withdrawal symptoms. Although the use of GLP-1RA could be beneficial in multiple ways, withdrawal after years has the symptoms reversed. Clinical studies should emphasize the downside of these views we highlighted, and mechanistic studies must be carried out for a better outcome with GLP-1RA from the laboratory to the bedside.

91Weight Regain After Liraglutide, Semaglutide or Tirzepatide Interruption: A Narrative Review of Randomized Studies.PubMed

Massimo Quarenghi, Silvia Capelli, Giulia Galligani, et al.
J Clin Med. 2025 May 28;14(11):3791. doi: 10.3390/jcm14113791.
The primary objective of this review is to analyze the effects on body weight of discontinuing therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or tirzepatide in patients treated for obesity. In recent months, there has been a considerable increase in the utilization of GLP-1 RAs and GIP/GLP-1 RAs. However, the paucity of available data regarding their medium- to long-term safety remains a salient concern. Of particular significance is the observation of the weight curve following their suspension, a subject that has received scant attention to date. : For this, a bibliographic search was carried out in three electronic databases: PubMed, Cochrane Library and Google Scholar. The following filters were applied: A total of 427 references were identified, 178 articles were read in full, and 13 articles were included in the analysis. : The analysis showed a rapid regain of weight after cessation of therapy, regardless of the duration of the treatment with GLP-1 RA or GIP/GLP-1 RA. This rebound is likely to substantially mitigate the metabolic benefits attained through weight loss. Given the efficacy of these drugs, it is essential for future research to focus on elucidating the optimal duration of these treatments or identifying techniques or schemes that involve a reduction in dosages to prevent weight regain.

92Self-reported Barriers to Adherence and Persistence to Treatment With Injectable Medications for Type 2 Diabetes.PubMed

C Victor Spain, Jonathon J Wright, Rebecca M Hahn, et al.
Clin Ther. 2016 Jul;38(7):1653-1664.e1. doi: 10.1016/j.clinthera.2016.05.009. Epub 2016 Jun 28.
PURPOSE: This study explored the barriers that adult Americans experience when taking injectable medications for type 2 diabetes, from the time of filling the initial prescription through the decision to discontinue the medication. METHODS: An Internet-based survey was conducted in 2 waves among adult patients (N = 2000) who had received a physician prescription for insulin, liraglutide, or exenatide once weekly (QW), regardless of whether the prescription was filled by a pharmacy. In wave 1, patients were surveyed on their medication history and experience and, if relevant, the medication discontinuation process. Those still taking their injectable medication at the time of wave 1 were contacted 6 months later (wave 2, n = 585) to assess any changes in their medication experience. FINDINGS: Among patients who delayed filling their prescription by ≥1 week, cost was a common reason for delay for refilling of liraglutide (63%) and exenatide QW (49%). The most commonly reported barrier to maintaining injectable medication was injection concerns (42%) such as aversion to needles, pain, or needle size. Lack of perceived need was the most common reason for discontinuation for basal (47%) and prandial/premixed (44%) insulin. For liraglutide, the most common reason for discontinuation was experiencing an adverse event (33%); for exenatide QW, it was injection concerns (38%). IMPLICATIONS: The diverse barriers we identified underscore the need for better patient-prescriber communication to ensure that newly prescribed injectable medications are consistent with a patient's ability or willingness to manage them, to appropriately set expectations about medications, and to address new barriers that arise during the course of treatment.

93Off-label antiobesity treatment in patients without diabetes with GLP-1 agonists in clinical practice.PubMed

N Sauer, F Reining, C Schulze Zur Wiesch, et al.
Horm Metab Res. 2015 Jul;47(8):560-564. doi: 10.1055/s-0034-1387793. Epub 2014 Sep 17.
The aim of the work was to investigate whether continuation of treatment, side effects, and effect on weight loss of GLP-1 agonists in obese patients without diabetes are equally promising in daily clinical-practice-settings compared to controlled clinical trials. Obese patients without diabetes of our interdisciplinary obesity centre were treated off-label with GLP-1-agonists for different time periods. Application was started with low-dose and increased if side effects were tolerable. Monthly costs were € 125 for daily applications of 1.2 mg liraglutide or 10 μg exenatide twice daily. Data were obtained by telephone interviews about baseline characteristics, weight loss, sensation of satiation, duration of therapy, side effects, and reasons for discontinuation. Of 43 included cases (5 males, mean age 43±11 years, mean weight 107±24 kg, mean excess weight 35±21 kg) 7 were treated with exenatide and 36 with liraglutide. Excess weight loss in linear regression models was 6.7% per month (p <0.05) under control of age, sex, initial weight, and type of GLP-1 analogue treatment and did not significantly differ between liraglutide and exenatide. Overall, 58% of patients reported side effects mostly concerning the gastrointestinal tract. Surprisingly no patient reported vomiting. One patient developed a severe pancreatitis. At time of telephone interview only 30.2% were continuing treatment. Mean treatment duration was 2.98±2.71 months. Common reasons for discontinuation of treatment were no/little effect on weight loss (27.9%), intolerable side effects (20.9%), or financial reasons (14%). GLP-1 agonist treatment in obese patients without diabetes also correlates with significant weight loss in clinical practice. However, side effects and discontinuation of treatment are common. Therefore, long-term effect on weight loss might not be as promising as suggested by data from clinical trials.

94Gestational Weight Gain and Pregnancy Outcomes After GLP-1 Receptor Agonist Discontinuation.PubMed

Jacqueline Maya, Deepti Pant, Yiran Fu, et al.
JAMA. 2025 Dec 23;334(24):2186-2196. doi: 10.1001/jama.2025.20951.
IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are contraindicated in pregnancy. Discontinuation of GLP-1RAs proximal to pregnancy could affect gestational weight gain and pregnancy outcomes. OBJECTIVE: To compare gestational weight gain and pregnancy outcomes with and without exposure to GLP-1RAs before or during early pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 149 790 singleton pregnancies delivered between June 1, 2016, and March 31, 2025, within a single academic health system. EXPOSURE: A GLP-1RA order between 3 years before and 90 days after conception, with propensity score matching of each exposed pregnancy to 3 unexposed pregnancies. MAIN OUTCOMES AND MEASURES: The primary outcome was gestational weight gain. Secondary outcomes were excess gestational weight gain, large and small for gestational age birth weight, birth weight percentile for gestational age and sex, birth length, preterm delivery, cesarean delivery, gestational diabetes, and hypertensive disorders of pregnancy. RESULTS: Among 149 790 pregnancies during the study period, 1792 (448 exposed and 1344 unexposed) were matched for the primary analysis. Exposed pregnancies had mean maternal age of 34.0 years (SD, 4.7 years) and prepregnancy body mass index of 36.1 (SD, 6.5; calculated as weight in kilograms divided by height in meters squared); 378 of 448 (84%) had obesity and 104 of 448 (23%) had preexisting diabetes; 136 (30%) were Hispanic, 49 (11%) were non-Hispanic Black, and 223 (50%) were non-Hispanic White; and 43 (10%) had public insurance. The GLP-1RA-exposed pregnancies had greater gestational weight gain (mean, 13.7 kg [SD, 9.2]) than propensity score-matched unexposed pregnancies (mean, 10.5 kg [SD, 8.0]), a difference of 3.3 kg (95% CI, 2.3-4.2; P < .001). The GLP-1RA-exposed group had a higher risk of excess gestational weight gain (65% vs 49%; risk ratio [RR], 1.32; 95% CI, 1.19-1.47), greater mean birth weight percentile (58.4% vs 54.8%; difference, 3.6%; 95% CI, 0.2%-6.9%), and higher risk of preterm delivery (17% vs 13%; RR, 1.34; 95% CI, 1.06-1.69), gestational diabetes (20% vs 15%; RR, 1.30; 95% CI, 1.01-1.68), and hypertensive disorders of pregnancy (46% vs 36%; RR, 1.29; 95% CI, 1.12-1.49). There was no difference in birth length, risk of large or small for gestational age birth weight, or cesarean delivery. CONCLUSIONS AND RELEVANCE: In a cohort composed primarily of women with obesity, GLP-1RA use with subsequent prepregnancy or early pregnancy discontinuation was associated with more gestational weight gain and a higher risk of preterm delivery, gestational diabetes, and hypertensive disorders of pregnancy.

95Exendin-4 enhances GLP-1 signaling and reduces anxiety-like behaviors in male heroin withdrawal mice.PubMed

Yang Xiang, Xiaowei Yan, Rongrong Li, et al.
PLoS One. 2026 Mar 12;21(3):e0343995. doi: 10.1371/journal.pone.0343995. eCollection 2026.
Anxiety and depression significantly contribute to heroin relapse, and addressing these issues could lower relapse rates. The basolateral amygdala (BLA) and nucleus tractus solitarius (NTS) are involved in regulating these emotions, but the molecular mechanisms during heroin withdrawal are not yet understood. Subcutaneous injection of heroin into C57BL/6J mice to simulate chronic dependence, withdrawal, and Exendin-4 treatment. Assess anxiety and depression-like behaviors using open field test (OFT), elevated plus maze (EPM), forced swimming test (FST), and tail suspension test (TST). Analyze neuronal and protein expression changes in the BLA brain area with Western blotting (WB) and immunofluorescence staining. Heroin dependence reduces glutamatergic neurons in BLA without affecting anxiety and depression-like behaviors, due to the inhibitory effect of heroin reward. During withdrawal, GLP-1 secretion by the NTS rises, increasing c-Fos and GLP-1 receptor expression in glutamatergic neurons of BLA, linked to heightened anxiety but not depression. A 7-day treatment with Exendin-4 (2 µg/kg) alleviates anxiety in withdrawal mice by downregulating GLP-1 signaling in the NTS-BLA circuit, indicating GLP-1's role in regulating anxiety during heroin withdrawal. GLP-1 receptors within BLA may serve as molecular targets for modulating emotional states, thereby offering empirical support for strategies aimed at preventing heroin relapse.

96Glucagon-like peptide-1 analogues: a new way to quit smoking? (SKIP)-a structured summary of a study protocol for a randomized controlled study.PubMed

Sophia Lengsfeld, Thilo Burkard, Andrea Meienberg, et al.
Trials. 2023 Apr 20;24(1):284. doi: 10.1186/s13063-023-07164-9.
BACKGROUND: Cigarette smoking is the leading preventable cause of premature death. Despite dedicated programmes, quit rates remain low due to barriers such as nicotine withdrawal syndrome or post-cessation weight gain. Glucagon-like peptide-1 (GLP-1) analogues reduce energy intake and body weight and seem to modulate addictive behaviour. These GLP-1 properties are of major interest in the context of smoking cessation. The aim of this study is to evaluate the GLP-1 analogue dulaglutide as a new therapy for smoking cessation. METHODS: This is a placebo-controlled, double-blind, parallel group, superiority, single-centre randomized study including 255 patients. The intervention consists of a 12-week dulaglutide treatment phase with 1.5 mg once weekly or placebo subcutaneously, in addition to standard of care (behavioural counselling and pharmacotherapy with varenicline). A 40-week non-treatment phase follows. The primary outcome is the point prevalence abstinence rate at week 12. Smoking status is self-reported and biochemically confirmed by end-expiratory exhaled carbon monoxide measurement. Further endpoints include post-cessational weight gain, nicotine craving analysis, glucose homeostasis and long-term nicotine abstinence. Two separate substudies assess behavioural, functional and structural changes by functional magnetic resonance imaging and measures of energy metabolism (i.e. resting energy expenditure, body composition). DISCUSSION: Combining behavioural counselling and medical therapy, e.g. with varenicline, improves abstinence rates and is considered the standard of care. We expect a further increase in quit rates by adding a second component of medical therapy and assume a dual effect of dulaglutide treatment (blunting nicotine withdrawal symptoms and reducing post-cessational weight gain). This project is of high relevance as it explores novel treatment options aimed at preventing the disastrous consequences of nicotine consumption and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT03204396 . Registered on June 26, 2017.

97A Comprehensive Review on the Pharmacokinetics and Drug-Drug Interactions of Approved GLP-1 Receptor Agonists and a Dual GLP-1/GIP Receptor Agonist.PubMed

Jee Sun Min, Seong Jun Jo, Sangyoung Lee, et al.
Drug Des Devel Ther. 2025 Apr 30;19:3509-3537. doi: 10.2147/DDDT.S506957. eCollection 2025.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

98An exploratory analysis of glucagon-like peptide-1 (GLP-1) agonists and biosimilars: A literature review.PubMed

Jimmy Wen, Adam Razick, Christiane How-Volkman, et al.
Diabetes Obes Metab. 2025 Mar;27(3):1113-1122. doi: 10.1111/dom.16110. Epub 2024 Dec 9.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are at the forefront of treating the global health crisis of diabetes mellitus (DM) and obesity. However, the demand for GLP-1 RAs has far outstripped its supply and comes with a high monthly cost. Thus, the development of GLP-1 RA biosimilars can potentially address these barriers by providing greater access to medications that provide clinical outcomes similar to those of the reference products. A narrative review was conducted to examine the current and future developments for GLP-1 RA biosimilars. Liraglutide and semaglutide are the predominant GLP-1 RAs being investigated for the development of biosimilars. Preliminary liraglutide biosimilar comparisons to reference liraglutide have demonstrated similar clinical efficacy and safety profiles. Semaglutide and beinaglutide biosimilars are currently under investigation as well. With the growing popularity of GLP-1 RAs, accessibility and affordability remain a challenge as monthly costs without insurance for liraglutide, semaglutide and tirzepatide are $1418, $892, and $974 respectively. This trend negatively impacts patients with obesity and DM as well as patients who can utilize it for off-label indications for conditions that benefit from weight loss such as obstructive sleep apnoea and non-alcoholic fatty liver disease. A substantial number of pharmaceutical and healthcare companies worldwide are conducting clinical trials on their GLP-1 RA biosimilars. Preliminary results from liraglutide biosimilars are promising, and several semaglutide biosimilars are currently being investigated. Future research should focus on conducting comparative head-to-head trials to determine the clinical outcomes between biosimilars and reference products.

99Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists.PubMed

Rasha Alhiary, Aaron S Kesselheim, Sarah Gabriele, et al.
JAMA. 2023 Aug 15;330(7):650-657. doi: 10.1001/jama.2023.13872.
IMPORTANCE: Glucagon-like peptide 1 (GLP-1) receptor agonists were first approved for the treatment of type 2 diabetes in 2005. Demand for these drugs has increased rapidly in recent years, as indications have expanded, but they remain expensive. OBJECTIVE: To analyze how manufacturers of brand-name GLP-1 receptor agonists have used the patent and regulatory systems to extend periods of market exclusivity. EVIDENCE REVIEW: The annual US Food and Drug Administration's (FDA) Approved Drug Products With Therapeutic Equivalence Evaluations was used to identify GLP-1 receptor agonists approved from 2005 to 2021 and to record patents and nonpatent statutory exclusivities listed for each product. Google Patents was used to extract additional data on patents, including whether each was obtained on the delivery device or another aspect of the product. The primary outcome was the duration of expected protection from generic competition, defined as the time elapsed from FDA approval until expiration of the last-to-expire patent or regulatory exclusivity. FINDINGS: On the 10 GLP-1 receptor agonists included in the cohort, drug manufacturers listed with the FDA a median of 19.5 patents (IQR, 9.0-25.8) per product, including a median of 17 patents (IQR, 8.3-22.8) filed before FDA approval and 1.5 (IQR, 0-2.8) filed after FDA approval. Fifty-four percent of all patents listed on GLP-1 receptor agonists were on the delivery devices rather than active ingredients. Manufacturers augmented patent protection with a median of 2 regulatory exclusivities (IQR, 0-3) obtained at approval and 1 (IQR, 0.3-4.3) added after approval. The median total duration of expected protection after FDA approval, when accounting for both preapproval and postapproval patents and regulatory exclusivities, was 18.3 years (IQR, 16.0-19.4). No generic firm has successfully challenged patents on GLP-1 receptor agonists to gain FDA approval. CONCLUSIONS AND RELEVANCE: Patent and regulatory reform is needed to ensure timely generic entry of GLP-1 receptor agonists to the market.

100Net prices of new antiobesity medications.PubMed

Inmaculada Hernandez, Sean D Sullivan
Obesity (Silver Spring). 2024 Mar;32(3):472-475. doi: 10.1002/oby.23973. Epub 2024 Jan 16.
OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP1s) are effective antiobesity drugs and the subject of intense debate around insurance coverage due to the large prevalence of obesity and overweight. The estimation of the budget impact associated with GLP1 insurance coverage requires estimates of GLP1 prices that account for manufacturer discounts. The authors applied a peer-reviewed method to estimate the net prices of GLP1s after manufacturer discounts. METHODS: The authors estimated manufacturer discounts for each product as the difference between the gross sales estimated at list price and manufacturer-reported revenue. From this difference, the authors subtracted discounts to government programs, including 340B, Medicaid, and the Medicare Part D coverage gap, and attributed the remaining amount to manufacturer discounts provided in the commercial market. RESULTS: Manufacturer discounts for GLP1s approved for obesity were estimated at 41%, which translated into net prices of $717 to $761 per month of supply. Manufacturer discounts for GLP1s approved for type 2 diabetes ranged from 54% to 59%, which translated into net prices of $312 to $469 per month of supply. CONCLUSIONS: The magnitude of manufacturer discounts underscores the need to consider net price information in studies that inform private and public payers' decision-making around coverage of GLP1s for obesity.

101Mazdutide: First Approval.PubMed

Matt Shirley
Drugs. 2025 Dec;85(12):1621-1627. doi: 10.1007/s40265-025-02249-y. Epub 2025 Sep 30.
Mazdutide (Xinermei) is a dual glucagon receptor (GcgR) and glucagon-like peptide-1 receptor (GLP-1R) agonist being developed by Eli Lilly and Company along with Innovent Biologics for use in weight management in adults with obesity or overweight and for the treatment of type 2 diabetes (T2D). In June 2025, mazdutide received its first approval, in China, for use (in combination with diet control and increased physical activity) in long-term body weight management in adults with a body-mass index (BMI) of ≥ 28 kg/m or with a BMI ≥ 24 kg/m together with one or more weight-related comorbidity. Subsequently, in September 2025, mazdutide also received approval in China for use in glycaemic control in adults with T2D. Additionally, mazdutide is under clinical evaluation for use in the treatment of metabolic dysfunction-associated fatty liver disease, obstructive sleep apnoea and alcohol use disorder. This article summarises the milestones in the development of mazdutide leading to this first approval for long-term body weight management in adults with obesity or overweight.

102Patent Thickets and Product Hops: Challenges and Opportunities for Legislative Reform.PubMed

William B Feldman
J Law Med Ethics. 2025 Apr 8:1-6. doi: 10.1017/jme.2025.54.
Two key strategies that brand-name pharmaceutical manufacturers employ to limit generic competition are patent thickets and product hops. The former strategy entails obtaining numerous patents on peripheral features of products (not just the active ingredients), and the latter involves shifting active ingredients into reformulations with new patent protection that can extend periods of market exclusivity. These strategies have become particularly problematic for drug-device combinations like inhalers and glucagon-like peptide-1 receptor agonists, which contain pharmaceutical compounds that are sold together with their delivery devices. The Senate Judiciary Committee moved three bipartisan bills out of committee during the last legislative session aimed at facilitating more timely generic competition. Although these bills offer a valuable step forward, more is needed to limit the sort of patent gamesmanship that has become pervasive in the US pharmaceutical industry. Such reforms should include routine reexamination by the US Patent and Trademark Office of patents submitted for listing with the Food and Drug Administration (FDA), a greater role for the FDA in reviewing such listings, limits on the number of patents that brand-name firms can assert when suing for infringement following patent challenges, stronger incentives for patent challenges, and more flexibility for the FDA to approve complex generic drugs.

103Carnitine Deficiency Caused by Salcaprozic Acid Sodium Contained in Oral Semaglutide in a Patient with Multiple Acyl-CoA Dehydrogenase Deficiency.PubMed

Yasuko Mikami-Saito, Masamitsu Maekawa, Masahiro Watanabe, et al.
Int J Mol Sci. 2025 Mar 25;26(7):2962. doi: 10.3390/ijms26072962.
Carnitine plays an essential role in maintaining energy homeostasis and metabolic flexibility. Various medications, such as pivalate-conjugated antibiotics, valproic acid, and anticancer agents, can induce carnitine deficiency, inhibit the utilization of fatty acid, and contribute to the development of hypoglycemia. No studies have linked oral semaglutide to carnitine deficiency. Herein, we report the case of a 34-year-old male patient with multiple acyl-CoA dehydrogenase deficiency who developed carnitine deficiency attributable to salcaprozic acid sodium (SNAC) in oral semaglutide. The patient was diagnosed with type 2 diabetes mellitus at 32 years of age and was treated with semaglutide injections. Hypoglycemic symptoms appeared after switching to oral semaglutide, and the mean levels of blood-free carnitine significantly decreased. Liquid chromatography-tandem mass spectrometry analysis revealed a peak corresponding to the SNAC-carnitine complex (/ 423.24) in the urine exclusively during the oral administration of semaglutide. The MS/MS spectra at / 423.24 contained peaks consistent with those of the SNAC and carnitine product ions. Our results suggest that through complexation with carnitine, SNAC may induce carnitine deficiency. Healthcare providers should monitor for carnitine deficiency when administering SNAC-containing medications to at-risk individuals. Furthermore, this case can raise more significant concerns about the potential impact of pharmaceutical excipients like SNAC on metabolic pathways.

104Self-Emulsifying delivery systems for oral administration of exenatide: Hydrophobic ion pairs vs. Dry reverse micelles.PubMed

Marlene Ramona Schmidt, Melanie Lena Ebert, Magnus Andre Kiechle, et al.
Int J Pharm. 2025 Jun 10;678:125711. doi: 10.1016/j.ijpharm.2025.125711. Epub 2025 May 11.
This research provides a comparative analysis of two innovative strategies - hydrophobic ion pairing (HIP) and dry reverse micelles (dRM) - to enhance the oral bioavailability of exenatide, a GLP-1 receptor agonist, as a diabetes treatment. These techniques were integrated into self-emulsifying drug delivery systems (SEDDS) featuring a lipid matrix composed of propylene glycol dilaurate and salicylic acid methyl ester (32.5 %:32.5 %; v/v) with polyethoxylated-35 castor oil (35 %; v/v) as surfactant. HIP enhances the lipophilicity of exenatide through ion-pairing with cationic surfactants, thereby promoting efficient incorporation into the lipid matrix of SEDDS. In contrast, dRM forms stabilized micellar structures using sorbitan monooleate, improving safety and compatibility. The droplet sizes for SEDDS were analyzed via dynamic light scattering and varied from 95 to 110 nm, with a polydispersity index of approximately 0.25, and zeta potentials between -1 mV and -6 mV. The maximum log D values were 2.13 ± 0.31 for exenatide-loaded HIPs (ExeHIP) and 2.05 ± 0.08 for exenatide-loaded dRM (ExedRM), indicating sufficient lipophilicity, which is crucial for effective absorption and bioavailability. Toxicological assessments showed low toxicity levels. In vivo studies indicated a relative bioavailability of 18.08 % for ExeHIP and 17.06 % for ExedRM compared to intravenous injection. Both strategies demonstrated a similar potential in relative bioavailability, reflecting a significant increase in bioavailability compared to the control. Notably, the HIP formulation provided better control over exenatide release and ensured stable GLP-1 levels, while dRMs are preferable for safety reasons as all excipients have GRAS status and are therefore FDA approved.

105Battle of GLP-1 delivery technologies.PubMed

Minzhi Yu, Mason M Benjamin, Santhanakrishnan Srinivasan, et al.
Adv Drug Deliv Rev. 2018 May;130:113-130. doi: 10.1016/j.addr.2018.07.009. Epub 2018 Jul 21.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.

106Current status of Liraglutide delivery systems for the management of type 2 diabetes mellitus.PubMed

Riti Chatterjee, Vishal Sangita Babasaheb Galave, Anil B Jindal
Drug Deliv Transl Res. 2025 Dec;15(12):4479-4500. doi: 10.1007/s13346-025-01965-y. Epub 2025 Sep 6.
Diabetes is a metabolic disorder of increasing global concern. Characterized by constantly elevated levels of glucose, severe β-cell dysfunction, and insulin resistance, it is the cause of a major burden on patients if not managed with therapeutic and lifestyle changes. The human body is slowly developing tolerance to many marketed antidiabetic drugs and the quest for the discovery of newer molecules continues. Liraglutide is a prominent GLP-1 receptor agonist which is administered daily via subcutaneous injection. In addition to lowering HbA1c levels, it is also known for promoting weight loss and improving cardiovascular outcomes. A variety of novel formulation strategies have been explored to improve its bioavailability and patient compliance. To address these limitations, various advanced drug delivery systems have been investigated, including polymeric nanoparticles, lipid-based nanocarriers, biodegradable microparticles, hydrogels, and dissolvable microneedles. These systems aim to prolong drug release, enhance mucosal penetration, increase stability, and reduce dosing frequency. While many of these platforms show promise in preclinical and early clinical studies, critical translational barriers remain. These include challenges in large-scale manufacturing, ensuring formulation sterility, achieving regulatory approval, and maintaining stability during storage and distribution.This review provides a comprehensive overview of the formulation strategies developed for liraglutide delivery, critically examines their pharmacokinetic and pharmacodynamic profiles, and evaluates the current state of clinical translation. By identifying both the potential and the limitations of these delivery technologies, the article aims to inform future research directions in GLP-1-based therapeutics and improve treatment outcomes for patients with T2DM.

107Enhancing the Therapeutic Efficacy of GLP-1 for Hyperglycemia Treatment: Overcoming Barriers of Oral Gene Therapy with Taurocholic Acid-Conjugated Protamine Sulfate and Calcium Phosphate.PubMed

S M Shatil Shahriar, Jeong Man An, Sachin S Surwase, et al.
ACS Nanosci Au. 2024 Apr 5;4(3):194-204. doi: 10.1021/acsnanoscienceau.3c00035. eCollection 2024 Jun 19.
Activating the glucagon-like peptide-1 (GLP-1) receptor by oral nucleic acid delivery would be a promising treatment strategy against hyperglycemia due to its various therapeutic actions. However, GLP-1 receptor agonists are effective only in subcutaneous injections because they face multiple barriers due to harsh gastrointestinal tract (GIT) conditions before reaching the site of action. The apical sodium bile acid transporter (ASBT) pathway at the intestinal site could be an attractive target to overcome the problem. Herein, we used our previously established multimodal carrier system utilizing bile salt, protamine sulfate, and calcium phosphate as excipients (PTCA) and the GLP-1 gene as an active ingredient (GENE) to test the effects of different formulation doses against diabetes and obesity. The carrier system demonstrated the ability to protect the GLP-1 model gene encoded within the plasmid at the GIT and transport it ASBT at the target site. A single oral dose, regardless of quantity, showed the generation of GLP-1 and insulin from the body and maintained the normoglycemic condition by improving insulin sensitivity and blood sugar tolerance for a prolonged period. This oral gene therapy approach shows significantly higher therapeutic efficacy in preclinical studies than currently available US Food and Drug Administration-approved GLP-1 receptor agonists such as semaglutide and liraglutide. Also, a single oral dose of GENE/PTCA is more effective than 20 insulin injections. Our study suggests that oral GENE/PTCA formulation could be a promising alternative to injection-based therapeutics for diabetics, which is effective in long-term treatment and has been found to be highly safe in all aspects of toxicology.

108Multi-target incretin-based therapeutics: The rise of dual and triple agonists for metabolic disorders.PubMed

Seyed Ebrahim Alavi, Reza Boshrouyeh, Aun Raza, et al.
Eur J Med Chem. 2026 Mar 5;305:118587. doi: 10.1016/j.ejmech.2026.118587. Epub 2026 Jan 13.
Dual and triple incretin-based therapies are transforming treatment for type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. By targeting glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors, these agents enhance glycemic control, reduce body weight, and improve liver outcomes. Drugs like tirzepatide and retatrutide have shown unprecedented efficacy and tolerability. This review summarizes their mechanisms, clinical progress, and limitations, highlighting how dual and triple incretin agonists may extend or refine the therapeutic benefits established by current GLP-1-based therapies. While challenges remain in safety, accessibility, and long-term use, multi-target agonists represent a promising future in metabolic disease management.

109Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes.PubMed

Robert M Gutgesell, Rubén Nogueiras, Matthias H Tschöp, et al.
Diabetes Ther. 2024 May;15(5):1069-1084. doi: 10.1007/s13300-024-01566-x. Epub 2024 Apr 4.
The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut-brain communication can be leveraged to achieve sustained body weight loss without adverse effects.

110Dual-Target Insight into Drug Discovery from Natural Products as Modulators of GLP-1 and the TXNIP-Thioredoxin Antioxidant System in Metabolic Syndrome.PubMed

Peter Chinedu Agu, Appolonia Fulgence Yudas, Jun Lu
Antioxidants (Basel). 2025 Nov 17;14(11):1364. doi: 10.3390/antiox14111364.
Metabolic Syndrome (MetS), a cluster of interconnected metabolic abnormalities, poses a growing global health burden. A well-established therapeutic target for the diseases is the incretin hormone glucagon-like peptide-1 (GLP-1); however, synthetic agonists have drawbacks such as expense, injectable administration, and side effects. Concurrently, one of the main pathogenic characteristics of MetS is oxidative stress, in which the Thioredoxin-Interacting Protein (TXNIP)/thioredoxin system is a critical player. The strong evidence that natural compounds derived from plant, marine, and microbiological sources can simultaneously target the TXNIP-thioredoxin antioxidant axis and GLP-1 signaling is examined in this study. These substances can limit TXNIP expression and increase thioredoxin activity while also stimulating GLP-1 secretion, inhibiting dipeptidyl peptidase-4 (DPP-4), or acting as GLP-1 receptor agonists. A cycle of reinforcement is created by these two actions: Pancreatic β-cell activity and incretin responsiveness are improved by GLP-1-mediated TXNIP downregulation, which also strengthens antioxidant defense. However, translational development must overcome major pharmacological obstacles, especially those related to bioavailability, metabolic stability, and standardization, despite encouraging preclinical effectiveness. To speed up this translational process, integrative computational techniques (such as molecular docking, network pharmacology, and artificial intelligence) are strong tools for lead optimization and creation of hypothesis. Thus, natural products can provide a special chance to discover multi-target treatments that comprehensively address the oxidative and hormonal causes of MetS.

111GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects.PubMed

Xin Zhao, Minghe Wang, Zhitong Wen, et al.
Front Endocrinol (Lausanne). 2021 Aug 23;12:721135. doi: 10.3389/fendo.2021.721135. eCollection 2021.
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

112GLP-1: Molecular mechanisms and outcomes of a complex signaling system.PubMed

Nicholas K Smith, Troy A Hackett, Aurelio Galli, et al.
Neurochem Int. 2019 Sep;128:94-105. doi: 10.1016/j.neuint.2019.04.010. Epub 2019 Apr 17.
Meal ingestion provokes the release of hormones and transmitters, which in turn regulate energy homeostasis and feeding behavior. One such hormone, glucagon-like peptide-1 (GLP-1), has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. In addition to the peripheral actions of GLP-1, this hormone is able to alter behavior through the modulation of multiple neural circuits. Recent work that focused on elucidating the mechanisms and outcomes of GLP-1 neuromodulation led to the discovery of an impressive array of GLP-1 actions. Here, we summarize the many levels at which the GLP-1 signal adapts to different systems, with the goal being to provide a background against which to guide future research.

113Bibliometric analysis of global research trends on the relationship between alzheimer's disease and type 2 diabetes mellitus.PubMed

Anderson Matheus Pereira da Silva, Maria da Santos do Nascimento, Gabriel Caruso Novaes Tudella, et al.
J Diabetes Metab Disord. 2025 Dec 23;25(1):12. doi: 10.1007/s40200-025-01812-4. eCollection 2026 Jun.
BACKGROUND: Background: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are highly prevalent chronic disorders with overlapping pathophysiological features. Increasing evidence suggests a bidirectional association, supported by shared mechanisms such as insulin resistance, neuroinflammation, and amyloid pathology giving rise to the concept of "type 3 diabetes." To map the global scientific output on the T2DM, AD relationship through a comprehensive bibliometric analysis, identifying publication trends, key contributors, and thematic developments. METHODS: A search was conducted in the Web of Science database on February 16, 2025, without time or language restrictions. Studies related to the association between T2DM and AD were retrieved and analyzed using VOSviewer and the Bibliometrix package in R. Metrics included publication volume, citation count, authorship, institutional affiliations, journal impact, and keyword co-occurrence. RESULTS: A total of 2,943 articles were identified, with a marked increase in output after 2011. The most cited article, by Craft et al., proposed a mechanistic link between insulin resistance and AD. The United States and China led in publication volume. Key institutions included Huazhong University of Science and Technology and Columbia University. Prominent authors included Hoelscher C and Liu Y. Keyword analysis revealed strong focus on "insulin resistance," "oxidative stress," and "neuroinflammation." Emerging trends included interest in GLP-1 receptor agonists, metformin, and biomarker-guided strategies. CONCLUSION: Research linking T2DM and AD has expanded substantially, reflecting growing recognition of shared mechanisms. Despite progress, gaps remain in biomarker integration and precision strategies. Future studies should emphasize longitudinal designs, mechanistic targets, and collaborative translational approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-025-01812-4.

114Japan initiates market authorization of weight‐loss drug semaglutide under universal health coverage, but with stringent prescription restrictionsOpenAlex

Hayase Hakariya, Mutsuko Ohnishi, Tetsuya Tanimoto
In November 2023, semaglutide (brand name Wegovy), a glucagon-like peptide-1 (GLP-1) receptor agonist, was granted regulatory approval for chronic weight management in Japan for the first time in Asian countries. Other Asian countries, such as China, are expected to introduce the drug shortly, and how authorities regulate weight-loss drugs is an internationally recognized concern. The drug has been covered by Japan's national universal health insurance since 22 February 2024 onwards under specific circumstances. The drug expense in Japan is less expensive compared with those in the United States or Europe; its monthly cost per patient without any reimbursement is about 1350 USD in the United States, 338 USD in Germany, and 290 USD in Japan (87 USD with national health insurance reimbursement). However, there is a concern about extremely limited patient access to the drug. In Japan, the drug is indicated for adult patients with either hypertension, hyperlipidaemia or type 2 diabetes mellitus who cannot achieve sufficient effect through dietary therapy and physical activity with an initial body mass index (BMI) of ≥35 kg/m2 or ≥27 kg/m2 in the presence of at least two weight-related comorbidities (Table 1).1 Although the prevalence of obesity in Japanese adults is low,2, 3 Japan's BMI criterion of ≥35 kg/m2 is more stringent and complicated compared with the United States or Europe. These countries allow an unconditional prescription for patients with a BMI of ≥30 kg/m2 (Table 1). Under this condition, Novo Nordisk, a manufacturer of Wegovy, estimates a 216 million USD (32.8 billion JPY) market in Japan, with 100 000 people being administered this drug at its peak. Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial BMI of for example, dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease Marketing authorization indication Semaglutide (Wegovy; Novo Nordisk) is indicated as an adjunct to a reduced calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial BMI of ≥30 kg/m2 (obesity), or ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity NICE recommendation Semaglutide is recommended as an option for weight management, including weight loss and weight maintenance, alongside a reduced-calorie diet and increased physical activity in adults, only if: they have at least 1 weight-related comorbidity and: In line with the drug's market authorization, the Japanese government issued a guideline to prevent inappropriate prescription of the drug,4 restricting the number of physicians who can prescribe the drug. In the background, the authorities are afraid of issues related to overuse, which have already been reported regarding out-of-pocket diet-purposed use where patients subscribe to semaglutide online outside of universal health coverage.5 Nonetheless, the guideline shows further concern for patient access to the drug. First, the guideline constrains institutions to be qualified educational training institutions that employ full-time medical doctors qualified by either of three obesity-related academic societies: Japan Diabetes Society, Japan Endocrine Society or Japan Circulation Society.4 This presumably indicates that only large, leading medical institutions, such as university hospitals, could be qualified for the guidelines. Therefore, patients cannot rely on their general practitioners in their nearby clinics. Second, for the first year on the market, physicians are only allowed to prescribe the drug for up to 2 weeks at a time, forcing patients to visit their doctors frequently.4 This would probably discourage patient compliance to see their doctors regularly (and frequently) because of the long waiting time in large hospitals in Japan. Third, unlike other countries, Japan imposes a maximum administration duration limit of 68 weeks for the drug,4 requiring physicians to carefully consider its prescription initiation. This duration restriction was simply set because no clinical trials have been reported to administer the drug over 68 weeks to Japanese individuals. Fourth, Japan's guidelines mandate that patients, in advance of the Wegovy administration, undergo dietary therapy and physical activity for a minimum of 6 months at the healthcare facility where the drug will be administered. This prerequisite underscores the importance of comprehensive obesity management and well-organized preparation. On the other hand, the restriction can become a barrier for patients, such as those with severe obesity who need immediate drug treatment or who have been receiving diet and physical therapy from their primary care physicians (who cannot prescribe Wegovy in most cases). Unlike Japan, the drug is available from family doctors in most European countries. However, similar restrictive attitudes towards the prescription of the drug are also observed among most European governments because of swelling health care budgets. Within Europe, the drug is available in Norway, Denmark, Germany, Switzerland, Iceland and the United Kingdom as of February 2024. Most of these countries do not reimburse the drug with national health insurance. Germany is one of the most stringent, prohibiting health insurance systems from paying out for weight-loss drugs under their legal system. It is reasonable for authorities to restrict the prescription to a certain extent, given the drug's high cost and international shortages of these injections because of the high demand, particularly in the United States.6-8 On the other hand, the United Kingdom will initiate a government pilot study from April 2024 to widen access to the drug, allowing general practitioners to prescribe the weight-loss drug to patients with obesity,9 despite concerns about shortages, particularly for patients with type 2 diabetes.10 This drug can currently be accessed only through specialist weight management services providing multidisciplinary management of overweight or obesity, which are largely hospital-based and prescribed for free.9 In the United States, general practitioners and nurse practitioners are generally allowed to prescribe the drug, and not a few private insurance companies cover it despite the high cost of the drug before the coverage. Such easy access has led to the drug being placed on the shortage list by the Food and Drug Administration (FDA). The shortage is expected to be addressed by Novo Nordisk's extended effort to boost supply, as well as the FDA's approval of tirzepatide (brand name Mounjaro), another GLP-1 receptor agonist developed by Eli Lily. There remains a discrepancy regarding the prescribing of this weight-loss drug, which necessitates further discussion. Nonetheless, Japan's stringent criteria contrast starkly in comparison with those of the United Kingdom and the United States, where individuals have the option of reimbursement. Japan should strike a balance between health care expenditures and ensuring access to newly introduced drugs to address the therapeutic needs of patients. Indeed, the drug has provided a benefit in reducing the incidence of heart attacks, strokes, or the risk of death from cardiovascular events for patients with pre-existing cardiovascular disease and overweight or obesity.11 In response to this evidence, the European Medical Agency and the US FDA started to consider a label expansion. Deregulation by Japan's regulatory body may be warranted to ensure the delivery of the drug to patients with indispensable needs, with balanced regulatory intervention for safeguarding equitable distribution and adequate pricing. H.H. is supported by the Toyobo Biotechnology Foundation Fellowship, outside the submitted work. Open Access funding enabled and organized by Projekt DEAL. TT receives personal fees from MNES Inc. and Bionics Inc., outside the submitted work. MO has no conflicts of interest to declare. HH is supported by the Toyobo Biotechnology Foundation Fellowship, outside the submitted work. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15638. The data that support the findings of this study are openly available in reference numbers 1, 4, and 12-15.

115Glucagon‑like peptide‑1 receptor agonists in multiple sclerosis: therapeutic promise, challenges, and future directions.PubMed

Afsaneh Shirani, Olaf Stuve
Expert Opin Investig Drugs. 2025 Nov;34(11):929-941. doi: 10.1080/13543784.2025.2587277. Epub 2025 Nov 10.
INTRODUCTION: This review evaluates the potential of glucagon‑like peptide‑1 receptor agonists (GLP‑1RAs) - first developed for type 2 diabetes and later approved for chronic weight management and additional indications - to be repurposed as neuroprotective and remyelinating therapies in multiple sclerosis (MS). We synthesize emerging pre‑clinical and early clinical evidence, highlight practical barriers to translation, and outline directions for future research. AREAS COVERED: In experimental autoimmune encephalomyelitis and toxin-induced demyelination mouse models, GLP-1RAs have been shown to reduce oxidative stress, preserve axonal integrity, suppress microglial and astrocytic activation, and, in some cases, promote remyelination. Early observational data in people with MS suggest GLP-1RAs are well tolerated, provide expected metabolic benefits, and do not exacerbate disease activity. Moreover, signals of reduced neurological impairment and lower dementia incidence in broader diabetic cohorts further support their translational promise. However, to date, there are no published randomized controlled trials of GLP-1RAs in MS. EXPERT OPINION: Pre‑clinical and early clinical signals support GLP‑1RAs as promising candidates for neuroprotection in MS, yet definitive evidence of disease‑modifying efficacy is lacking. Practical barriers, such as drug availability and cost, together with unresolved mechanistic questions underscore the need for biomarker‑rich mechanistic trials. Rigorous prospective studies are essential to establish whether GLP‑1RAs can meaningfully alter the trajectory of MS.

116The 'Obesity First' approach: Redefining the future of healthcare.PubMed

Chris J J Mulder, Ahmed B Bayoumy, Azhar R Ansari
Indian J Gastroenterol. 2026 Feb;45(1):15-19. doi: 10.1007/s12664-025-01882-5. Epub 2025 Oct 28.
Obesity is a highly prevalent, chronic disease driven by food addiction and associated with increased premature mortality. Obesogenic environments promote unhealthy behavior, making weight management challenging. Until recently, effective pharmacological treatments were lacking. The introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represents a major breakthrough in obesity care, with the potential to transform treatment strategies. Despite their efficacy, high costs (as of 2025) limit accessibility, particularly in low and middle-income regions, where parallel, unregulated use is emerging. Obesity remains under-recognized as a primary medical condition, especially in populations prone to metabolic complications, including metabolic dysfunction-associated steatotic liver disease (MASLD). Gastroenterology has historically underestimated the role of GLP-1 RAs in the past. Moving forward, the choice between GLP-1 therapy and bariatric endoscopy/surgery will become a central research focus, with treatment failures in one modality already leading to crossover. GLP-1 RAs are expected to significantly impact obesity-related comorbidities, including hypertension, dyslipidaemia, type-2 diabetes, sleep apnea, MASLD and inflammatory bowel disease (IBD). An "Obesity First" approach may reshape healthcare by addressing obesity as the primary topic cause for chronic disease. By 2035, the role of GLP-1 RAs as potential lifelong treatment will become clearer, with generic market expansion anticipated following patent expirations (China 2026; Europe 2031).

117Bypassing Prescribers and Pharmacists: Online Purchasing of Semaglutide and Tirzepatide "For Research Purposes".PubMed

Jordyn Belcourt, Priscilla Ly, C Michael White
Ann Pharmacother. 2025 May;59(5):485-490. doi: 10.1177/10600280241277551. Epub 2024 Sep 17.
Unscrupulous manufacturers provide consumers with ways to circumvent access controls by purchasing drug products outside the legitimate prescription drug supply chain. Manufacturers are selling vials containing semaglutide and tirzepatide to consumers without a prescription for "research purposes only" and/or "not for human consumption," but frequently without the supplies and knowledge they would need to dissolve the active ingredient, draw it up into a syringe, and inject it into the body. Avoiding prescribers allows consumer access to products where the risk may outweigh the benefits and quality standards may not be met. It also makes it difficult to prevent drug interactions or perform adequate patient monitoring and follow-up.

118Multifactor Quality and Safety Analysis of Semaglutide Products Sold by Online Sellers Without a Prescription: Market Surveillance, Content Analysis, and Product Purchase Evaluation Study.PubMed

Amir Reza Ashraf, Tim Ken Mackey, Róbert György Vida, et al.
J Med Internet Res. 2024 Nov 7;26:e65440. doi: 10.2196/65440.
BACKGROUND: Over the past 4 decades, obesity has escalated into a global epidemic, with its worldwide prevalence nearly tripling. Pharmacological treatments have evolved with the recent development of glucagon-like peptide 1 agonists, such as semaglutide. However, off-label use of drugs such as Ozempic for cosmetic weight loss has surged in popularity, raising concerns about potential misuse and the emergence of substandard and falsified products in the unregulated supply chain. OBJECTIVE: This study aims to conduct a multifactor investigation of product quality and patient safety risks associated with the unregulated online sale of semaglutide by examining product availability and vendor characteristics and assessing product quality through test purchases. METHODS: We used a complex risk and quality assessment methodology combining online market surveillance, search engine results page analysis, website content assessment, domain traffic analytics, conducting targeted product test purchases, visual quality inspection of product packaging, microbiological sterility and endotoxin contamination evaluation, and quantitative sample analysis using liquid chromatography coupled with mass spectrometry. RESULTS: We collected and evaluated 1080 links from search engine results pages and identified 317 (29.35%) links belonging to online pharmacies, of which 183 (57.7%) led to legal pharmacies and 134 (42.3%) directed users to 59 unique illegal online pharmacy websites. Web traffic data for the period between July and September 2023 revealed that the top 30 domains directly or indirectly affiliated with illegal online pharmacies accumulated over 4.7 million visits. Test purchases were completed from 6 illegal online pharmacies with the highest number of links offering semaglutide products for sale without prescription at the lowest price range. Three injection vial purchases were delivered; none of the 3 Ozempic prefilled injection pens were received due to nondelivery e-commerce scams. All purchased vials were considered probable substandard and falsified products, as visual inspection indicated noncompliance in more than half (59%-63%) of the evaluated criteria. The semaglutide content of samples substantially exceeded labeled amounts by 28.56%-38.69%, although no peptide-like impurities were identified. The lyophilized peptide samples were devoid of viable microorganisms at the time of testing; however, endotoxin was detected in all samples with levels ranging between 2.1645 EU/mg and 8.9511 EU/mg. Furthermore, the measured semaglutide purity was significantly low, ranging between 7.7% and 14.37% and deviating from the 99% claimed on product labels by manufacturers. CONCLUSIONS: Glucagon-like peptide 1 agonist drugs promoted for weight loss, similar to erectile dysfunction medications more than 2 decades ago, are becoming the new blockbuster lifestyle medications for the illegal online pharmacy market. Protecting the pharmaceutical supply chain from substandard and falsified weight loss products and raising awareness regarding online medication safety must be a public health priority for regulators and technology platforms alike.

119GLP-1 Receptor Agonists in Brazil: Landscape of Consumption, Safety and Regulation.PubMed

Renato Lopes Hurtado, Angélica Amorim Amato, Hugo de Luca Corrêa, et al.
Diabetes Obes Metab. 2026 May;28(5):4185-4193. doi: 10.1111/dom.70609. Epub 2026 Mar 8.
BACKGROUND: The escalating use of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is reshaping pharmaceutical consumption patterns and posing unprecedented challenges to healthcare systems worldwide. This study analyzes the landscape of GLP-1 RA consumption, safety monitoring and regulatory oversight in Brazil. METHODS: A retrospective regulatory surveillance study was carried out triangulating data from three official sources: (1) national sales covering 2020-2024, classifying according to Anatomical Therapeutic Chemical (ATC) system; (2) adverse event reports submitted to Vigimed, the national pharmacovigilance platform integrated with global VigiBase; and (3) official alerts of falsified products. Sales data were sourced from industrial reports and the National System for the Management of Controlled Products (SNGPC). RESULTS: Semaglutide emerged as the predominant GLP-1 RA in the Brazilian market. Consumption was markedly concentrated in regions with higher Gross Domestic Product (GDP), revealing a disconnect between medication use and regional diabetes prevalence. Pharmacovigilance analysis uncovered a significant proportion of reports involving off-label use, pointing to potential clinical and regulatory gaps. Furthermore, documented cases of counterfeit products underscore critical supply chain vulnerabilities. CONCLUSION: The convergence of escalating demand, widespread off-label use and product falsification requires a coordinated and agile regulatory response. The observed trends suggest significant access disparities driven by economic factors rather than epidemiological need.

120WHO Warns of Counterfeit Ozempic in the Global Supply Chain-Here's What to Know.PubMed

Kate Ruder
JAMA. 2024 Aug 13;332(6):442-443. doi: 10.1001/jama.2024.13507.